U.S. patent number 6,953,793 [Application Number 09/927,324] was granted by the patent office on 2005-10-11 for substituted pyrazoles.
This patent grant is currently assigned to Ortho-McNeil Pharmaceutical, Inc.. Invention is credited to Christopher R. Butler, Hui Cai, James P. Edwards, Cheryl A. Grice, Darin J. Gustin, Haripada Khatuya, Steven P. Meduna, Barbara A. Pio, Clark A. Sehon, Kevin L. Tays, Jianmei Wei.
United States Patent |
6,953,793 |
Butler , et al. |
October 11, 2005 |
Substituted pyrazoles
Abstract
Substituted pyrazoles, methods of manufacturing them,
compositions containing them, and methods of using them to treat,
for example, autoimmune diseases mediated by cathepsin S are
described.
Inventors: |
Butler; Christopher R. (San
Diego, CA), Cai; Hui (San Diego, CA), Edwards; James
P. (San Diego, CA), Grice; Cheryl A. (Carlsbad, CA),
Gustin; Darin J. (San Diego, CA), Khatuya; Haripada (San
Diego, CA), Meduna; Steven P. (San Diego, CA), Pio;
Barbara A. (San Diego, CA), Sehon; Clark A. (San Diego,
CA), Tays; Kevin L. (Cardiff, CA), Wei; Jianmei (San
Diego, CA) |
Assignee: |
Ortho-McNeil Pharmaceutical,
Inc. (Raritan, NJ)
|
Family
ID: |
26919364 |
Appl.
No.: |
09/927,324 |
Filed: |
August 10, 2001 |
Current U.S.
Class: |
514/217.09;
548/364.1; 514/230.5; 544/284; 546/211; 546/119; 544/105; 514/326;
540/603; 514/422; 514/266.21; 514/303 |
Current CPC
Class: |
A61P
37/00 (20180101); C07D 471/04 (20130101); A61K
31/4155 (20130101); A61P 19/02 (20180101); A61P
37/06 (20180101); A61P 11/06 (20180101); A61K
31/275 (20130101); A61K 31/454 (20130101); A61K
31/495 (20130101); C07D 413/14 (20130101); C07D
471/14 (20130101); A61P 43/00 (20180101); A61K
31/55 (20130101); A61P 29/00 (20180101) |
Current International
Class: |
A61K
31/495 (20060101); A61K 31/4523 (20060101); A61K
31/55 (20060101); A61K 31/454 (20060101); A61K
31/275 (20060101); C07D 471/00 (20060101); A61K
31/4155 (20060101); C07D 471/14 (20060101); C07D
471/04 (20060101); C07D 413/14 (20060101); C07D
413/00 (20060101); C07D 519/00 (20060101); A61K
031/454 (); C07D 403/06 () |
Field of
Search: |
;544/109,284 ;540/603
;546/119,211 ;548/264.1 ;514/217.09,230.5,266.21,303,326,422 |
References Cited
[Referenced By]
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WO |
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|
Primary Examiner: Raymond; Richard L.
Parent Case Text
This application claims benefit of U.S. Provisional Application No.
60/225,178 filed Aug. 14, 2000.
Claims
What is claimed is:
1. A compound of formula I: ##STR66##
wherein: Ar.sub.2 is a monocyclic or bicyclic ring system,
unsaturated, saturated or aromatic, optionally fused, optionally
including between 1 and 5 heteroatom ring moieties independently
selected from O, S, N, SO.sub.2, and C.dbd.O; said Ar.sub.2 ring
system being optionally substituted with between 1 and 4
substituents, provided that when Ar.sub.2 is a bicyclic ring
system, then said bicyclic ring system has an attachment ring
attached to W at an attachment member of said attachment ring, said
attachment member is a heteroatom selected from O, S, and N, or a
carbon member, and further provided that when said attachment
member is a carbon member, then said attachment ring has either (a)
at least two heteroatom ring moieties independently selected from
O, S, N, SO.sub.2, and C.dbd.O, or (b) said attachment ring system
has one heteroatom ring moiety selected from O, S, N, SO.sub.2, and
C.dbd.O, and said heteroatom ring moiety is directly attached to
said attachment member; R.sup.5 and R.sup.6 are independently
selected from hydrogen and C.sub.1-5 alkyl; R.sup.7 and R.sup.8 are
independently hydrogen, C.sub.1-5 alkyl, C.sub.2-5 alkenyl,
C.sub.1-5 alkoxy, C.sub.1-5 alkylthio, halogen, or a 4-7 membered
carbocyclyl or heterocyclyl; alternatively, R.sup.7 and R.sup.8 can
be taken together to form an optionally substituted 5- to
7-membered carbocyclic or heterocyclic ring, which ring may be
unsaturated or aromatic, and may be optionally substituted with
between one and three substituents independently selected from
halo, cyano, amino, hydroxy, nitro, R.sup.4, R.sup.4 O--, R.sup.4
S--, R.sup.4 O(C.sub.1-5 alkylene)-, R.sup.4 O(C.dbd.O)--, R.sup.4
(C.dbd.O)--, R.sup.4 (C.dbd.S)--, R.sup.4 (C.dbd.O)O--, R.sup.4
O(C.dbd.O)(C.dbd.O)--, R.sup.4 SO.sub.2, NHR.sup.44 SO.sub.2 --,
and NHR.sup.44 (C.dbd.O)--; R.sup.4 is H, C.sub.1-5 alkyl,
C.sub.2-5 alkenyl, C.sub.1-5 heterocyclyl, (C.sub.1-5
heterocyclyl)C.sub.1-6 alkylene, phenyl, benzyl, phenethyl,
NH.sub.2, mono- or di(C.sub.1-6 alkyl)N--, or R.sup.42 OR.sup.43
--, wherein R.sup.42 is H, C.sub.1-5 alkyl, C.sub.2-5 alkenyl,
phenyl, benzyl, phenethyl, C.sub.1-5 heterocyclyl, or (C.sub.1-5
heterocyclyl)C.sub.1-6 alkylene and R.sup.43 is C.sub.1-5 alkylene,
phenylene, or divalent C.sub.1-5 heterocyclyl; R.sup.44 is any one
of the values for R.sup.4 ; n is 0, 1, or 2; G is C.sub.3-6
alkenediyl or straight C.sub.3-6 alkanediyl, optionally substituted
with hydroxy, halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, oxo,
hydroximino, CO.sub.2 R.sup.k, R.sup.k R.sup.l N, R.sup.k R.sup.l
NCO.sub.2, (L)-C.sub.1-4 alkylene-, (L)-C.sub.1-5 alkoxy, N.sub.3,
or [(L)-C.sub.1-5 alkylene]amino; each of R.sup.k and R.sup.l is
independently hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl,
benzyl, phenethyl, or C.sub.1-5 heterocyclyl; alternatively R.sup.k
and R.sup.l, can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring, which ring may be
saturated, unsaturated or aromatic; L is amino, mono- or
di-C.sub.1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl
homopiperidinyl, or piperazinyl, wherein available ring nitrogens
may be optionally substituted with C.sub.1-5 alkyl, benzyl,
C.sub.2-5 acyl, C.sub.1-5 alkylsulfonyl, or C.sub.1-5
alkoxycarbonyl; Ar represents a monocyclic or bicyclic aryl or
heteroaryl ring, optionally substituted with between 1 and 3
substituents independently selected from halogen, C.sub.1-5 alkoxy,
C.sub.1-5 alkyl, C.sub.2-5 alkenyl, cyano, nitro, R.sup.22 R.sup.23
N, R.sup.24 SO.sub.2, R.sup.24 S, R.sup.24 SO, R.sup.24 OC.dbd.O,
R.sup.22 R.sup.23 NC.dbd.O, C.sub.1-5 haloalkyl, C.sub.1-5
haloalkoxy, C.sub.1-5 haloalkylthio, and C.sub.1-5 alkylthio;
R.sup.22 is hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl,
phenethyl, benzyl, or C.sub.1-5 heterocyclyl, C.sub.2-8 acyl,
aroyl, R.sup.38 OC.dbd.O, R.sup.25 R.sup.26 NC.dbd.O, R.sup.38 SO,
R.sup.38 SO.sub.2, R.sup.38 S, or R.sup.25 R.sup.26 NSO.sub.2 ;
R.sup.38 is H, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl,
phenethyl, or C.sub.1-5 heterocyclyl; R.sup.23 is hydrogen,
C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl or C.sub.1-5
heterocyclyl; alternatively, R.sup.22 and R.sup.23 can be taken
together to form an optionally substituted 4- to 7-membered
heterocyclic ring, which ring may be saturated, unsaturated or
aromatic; R.sup.24 is C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl,
benzyl, or C.sub.1-5 heterocyclyl; R.sup.25 and R.sup.26
independently are hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl,
phenyl, benzyl, or C.sub.1-5 heterocyclyl; or, alternatively,
R.sup.25 and R.sup.26 can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring, which ring may be
saturated, unsaturated or aromatic; W represents O, S, NR.sup.27,
C.dbd.O, (C.dbd.O)NH, NH(C.dbd.O), CHR.sup.28, or a covalent bond;
R.sup.z is H or OH and the dashed line is absent; or R.sup.z is
absent where the dashed line is an sp.sup.2 bond; R.sup.27 is
hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, naphthyl,
benzyl, phenethyl, C.sub.1-5 heterocyclyl, C.sub.2-8 acyl, aroyl,
R.sup.29 OC.dbd.O, R.sup.30 R.sup.31 NC.dbd.O, R.sup.29 SO,
R.sup.29 S, R.sup.29 SO.sub.2, or R.sup.30 R.sup.31 NSO.sub.2 ; or,
alternatively, R.sup.27 and part of Ar.sub.2 can be taken together
to form an optionally substituted 5- or 6-membered heterocyclic
ring with optionally 1 to 3 additional heteroatom moieties in the
ring selected from O, NR.sup.9, NR.sup.10, N, SO.sub.2, C.dbd.O,
and S; which ring may be saturated, unsaturated or aromatic;
R.sup.9 and R.sup.10 are independently selected from H, C.sub.1-3
alkyl, and --CH.sub.2 CO.sub.2 (C.sub.1-4 alkyl); R.sup.28 is
hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, hydroxy, phenyl,
benzyl, C.sub.1-5 heterocyclyl, R.sup.29 O, R.sup.30 R.sup.31
NC.dbd.O, R.sup.29 S, R.sup.29 SO, R.sup.29 SO.sub.2, or R.sup.30
R.sup.31 NSO.sub.2 ; R.sup.29 is C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, or C.sub.1-5 heterocyclyl; R.sup.30 and
R.sup.31 are independently selected from hydrogen, C.sub.1-5 alkyl,
C.sub.3-5 alkenyl, phenyl, benzyl, phenethyl, naphthyl, and
C.sub.1-5 heteroaryl; alternatively, R.sup.30 and R.sup.31 can be
taken together to form an optionally substituted 4- to 7-membered
ring carbocyclic or heterocyclic ring, which ring may be saturated,
unsaturated or aromatic; wherein each of the above hydrocarbyl or
heterocarbyl groups, unless otherwise indicated, and in addition to
any specified substituents, is optionally and independently
substituted with between 1 and 3 substituents selected from methyl,
halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano,
C.sub.1-5 alkyl, C.sub.1-5 alkoxy, --COOH, C.sub.2-6 acyl,
[di(C.sub.1-4 alkyl)amino]C.sub.2-5 alkylene, [di(C.sub.1-4
alkyl)amino]C.sub.2-5 alkyl-NH--CO--, and C.sub.1-5 haloalkoxy; or
a pharmaceutically acceptable salt, amide, or ester thereof; or a
stereoisomeric form thereof.
2. A compound of claim 1, wherein Ar.sub.2 is selected from 5-7
membered monocyclic rings, and [5,6], [6,6], [6,5], and [5,5] fused
bicyclic ring systems, said ring or ring system being carbocyclic
or heterocyclic, saturated, unsaturated, or aromatic, optionally
substituted with halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 hydroxyalkyl, nitro, hydroxy, amino, mono- or
di-(C.sub.1-6 alkyl)amino, C.sub.1-4 alkoxy, C.sub.2-4
alkoxycarbonyl, C.sub.2-6 acyl, C.sub.2-6 acyloxy, C.sub.1-5
alkylsulfonyl, C.sub.1-5 alkoxycarbonyl C.sub.1-4 alkoxy, cyano,
and mono- or di-(C.sub.1-6 alkyl)carbamoyl.
3. A compound of claim 1, wherein Ar.sub.2 is selected from
2,5-di(C.sub.1-6 alkyl)aminopyrrolyl and the following 6 formulae:
##STR67##
wherein each dashed line may be an sp.sup.2 bond or absent; X.sub.c
is O, S, or N; and X.sub.d is O or S; R.sup.1 is hydrogen, halogen,
C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, C.sub.2-5 alkenyl,
cyano, nitro, R.sup.a R.sup.b N, C.sub.2-8 acyl, C.sub.1-5
heterocyclyl, (C.sub.1-5 heterocyclyl)C.sub.1-5 alkylene, R.sup.11
S, R.sup.11 SO, R.sup.11 SO.sub.2, R.sup.c OC.dbd.O, R.sup.c
R.sup.d NC.dbd.O, or R.sup.c R.sup.d NSO.sub.2 ; or R.sup.1 can be
taken together with R.sup.27 as provided below; R.sup.2 is
hydrogen, halogen, C.sub.1-5 alkony, hydroxy, C.sub.1-5 alkyl,
C.sub.2-5 alkenyl, cyano, nitro, R.sup.e R.sup.f N, C.sub.1-5
heterocyclyl, or C.sub.2-8 acyl; R.sup.3 is hydrogen, halogen,
C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, C.sub.2-5 alkenyl,
cyano, nitro, R.sup.g R.sup.h N, C.sub.2-8 acyl, C.sub.1-5
heterocyclyl, R.sup.h OC.dbd.O, R.sup.g R.sup.h NC.dbd.O, or
R.sup.g R.sup.h NSO.sub.2 ; R.sup.a is selected from hydrogen,
C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl, phenethyl,
C.sub.1-5 heterocyclyl, C.sub.2-8 acyl, aroyl, R.sup.j OC.dbd.O,
R.sup.i R.sup.j NC.dbd.O, R.sup.12 SO, R.sup.12 SO.sub.2, R.sup.12
S, and R.sup.i R.sup.j NSO.sub.2 ; R.sup.e is selected from
hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl,
phenethyl, C.sub.1-5 heterocyclyl, C.sub.2-8 acyl, aroyl, R.sup.32
OC.dbd.O, R.sup.32 R.sup.33 NC.dbd.O, R.sup.13 SO, R.sup.13
SO.sub.2, R.sup.13 S, and R.sup.32 R.sup.33 NSO.sub.2 ; R.sup.m is
selected from hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl,
benzyl, phenethyl, C.sub.1-5 heterocyclyl, C.sub.2-8 acyl, aroyl,
R.sup.34 OC.dbd.O, R.sup.34 R.sup.35 NC.dbd.O, R.sup.15 SO,
R.sup.15 SO.sub.2, R.sup.15 S and R.sup.34 R.sup.35 NSO.sub.2 ;
R.sup.o is selected from hydrogen, C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, phenethyl, C.sub.1-5 heterocyclyl,
C.sub.2-8 acyl, aroyl, R.sup.36 OC.dbd.O, R.sup.36 R.sup.37
NC.dbd.O, R.sup.19 SO, R.sup.19 SO.sub.2, R.sup.19 S, and R.sup.36
R.sup.37 NSO.sub.2 ; each of R.sup.b, R.sup.f, R.sup.n, R.sup.p,
R.sup.32, R.sup.33, R.sup.34, R.sup.35, R.sup.36, R.sup.37,
R.sup.39, and R.sup.40 is independently selected from hydrogen,
C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl, phenethyl, and
C.sub.1-5 heteroaryl; alternatively, R.sup.a and R.sup.b, R.sup.e
and R.sup.f, R.sup.m and R.sup.n, and R.sup.o and R.sup.p,
independently, can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring, which ring may be
saturated, unsaturated or aromatic; each of R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.19, R.sup.38, and
R.sup.41 is independently C.sub.1-5 alkyl, C.sub.3-5 alkenyl,
phenyl, benzyl, phenethyl, or C.sub.1-5 heterocyclyl; each of
R.sup.c and R.sup.d, and R.sup.i and R.sup.j are independently are
hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl,
phenethyl, or C.sub.1-5 heteroaryl; alternatively, R.sup.c and
R.sup.d, and R.sup.i and R.sup.j, independently, can be taken
together to form an optionally substituted 4- to 7-membered
heterocyclic ring, which ring may be saturated, unsaturated or
aromatic; R.sup.g is hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl,
phenyl, benzyl, phenethyl, or C.sub.1-5 heterocyclyl, C.sub.2-8
acyl, aroyl, R.sup.17 OC.dbd.O, R.sup.17 R.sup.18 NC.dbd.O,
R.sup.16 S, R.sup.16 SO, R.sup.16 SO.sub.2, or R.sup.17 R.sup.18
NSO.sub.2 ; R.sup.h is hydrogen, C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, phenethyl or C.sub.1-5 heterocyclyl;
alternatively, R.sup.g and R.sup.h can be taken together to form an
optionally substituted 4- to 7-membered heterocyclic ring, which
ring may be saturated, unsaturated or aromatic; R.sup.17 and
R.sup.18 independently are hydrogen, C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, or C.sub.1-5 heterocyclyl; alternatively,
R.sup.17 and R.sup.18 can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring, which ring may be
saturated, unsaturated or aromatic; Y.sub.e is nitrogen or R.sup.20
C; Z.sub.e is nitrogen or R.sup.21 C; R.sup.20 is hydrogen,
halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, C.sub.2-5 alkenyl,
cyano, nitro, R.sup.m R.sup.n N, C.sub.2-8 acyl, R.sup.m OC.dbd.O,
R.sup.14 S, R.sup.14 SO, or R.sup.14 SO.sub.2 ; R.sup.21 is
hydrogen, halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, C.sub.2-5
alkenyl, cyano, nitro, R.sup.o R.sup.p N, C.sub.2-8 acyl, R.sup.16
OC.dbd.O, R.sup.11 S, R.sup.11 SO, or R.sup.11 SO.sub.2 ;
alternatively, R.sup.3 and R.sup.20 or R.sup.3 and R.sup.21 can be
taken together to form an optionally substituted 5- or 6-membered
carbocyclic or heterocyclic ring, which ring may be saturated,
unsaturated or aromatic; wherein said ring may be optionally
substituted with halo, di(C.sub.1-5 alkyl)amino, C.sub.2-5 acyl,
and C.sub.1-5 alkoxy; R.sup.27 is hydrogen, C.sub.1-5 alkyl,
C.sub.3-5 alkenyl, phenyl, naphthyl, benzyl, phenethyl, C.sub.1-5
heterocyclyl, C.sub.2-8 acyl, aroyl, R.sup.29 OC.dbd.O, R.sup.30
R.sup.31 NC.dbd.O, R.sup.29 SO, R.sup.29 S, R.sup.29 SO.sub.2, or
R.sup.30 R.sup.31 NSO.sub.2 ; or, alternatively, R.sup.27 and
R.sup.1 can be taken together to form an optionally substituted 5-
or 6-membered heterocyclic ring with optionally 1 to 3 additional
heteroatom moieties in the ring selected from O, NR.sup.9,
NR.sup.10, N, SO.sub.2, C.dbd.O, and S; which ring may be
saturated, unsaturated or aromatic; R.sup.9 and R.sup.10 are
independently selected from H, C.sub.1-3 alkyl, and --CH.sub.2
CO.sub.2 (C.sub.1-4 alkyl); X.sub.f is CHR.sup.1f, .dbd.N--, NH,
C.dbd.O, SO.sub.2, CHSR.sup.1f wherein, in formula (f), R.sup.1f is
hydrogen, halogen, C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl,
C.sub.3-5 alkenyl, cyano, nitro, R.sup.39 R.sup.40 N, C.sub.2-8
acyl, C.sub.1-5 heterocyclyl, (C.sub.1-5 heterocyclyl)C.sub.1-5
alkylene, R.sup.41 S, R.sup.41 SO, R.sup.41 SO.sub.2, R.sup.39
OC.dbd.O, R.sup.39 R.sup.40 NC.dbd.O, R.sup.39 R.sup.40 NSO.sub.2,
R.sup.41 SO.sub.3 -- or R.sup.39 (C.dbd.O)O--; Y.sub.f is CH.sub.2,
CHR.sup.2f, .dbd.CR.sup.2f, O, or NR.sup.2f, wherein R.sup.2f is H,
C.sub.1-5 alkyl, C.sub.3-5 alkenyl, C.sub.2-8 acyl, C.sub.1-5
heterocyclyl, (C.sub.1-5 heterocyclyl)-C.sub.1-5 alkylene,
C.sub.1-5 haloalkyl, C.sub.1-5 cyanoalkyl, (C.sub.1-5
alkoxycarbonyl)C.sub.1-5 alkylene, and (phenylcarbonyl)NH--; m is 0
or 1; p is 0 or 1; wherein each of the above hydrocarbyl or
heterocarbyl groups, unless otherwise indicated, and in addition to
any specified substituents, is optionally and independently
substituted with between 1 and 3 substituents selected from methyl,
halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano,
C.sub.1-5 alkyl, C.sub.1-5 alkoxy, --COOH, C.sub.2-6 acyl,
[di(C.sub.1-4 alkyl)amino]C.sub.2-5 alkylene, [di(C.sub.1-4
alkyl)amino]C.sub.2-5 alkyl-NH--CO--, and C.sub.1-5 haloalkoxy.
4. A compound of claim 3, wherein Ar.sub.2 is selected from
formulae (e).
5. A compound of claim 3, wherein Ar.sub.2 is selected from
formulae (f).
6. A compound of claim 3, wherein Ar.sub.2 is selected from formula
(a)-(d).
7. A compound of claim 3, wherein R.sup.1 is halogen, C.sub.1-5
alkoxy, hydroxy, C.sub.1-5 alkyl, cyano, nitro, R.sup.a R.sup.b N
or is taken together with R.sup.27.
8. A compound of claim 7, wherein R.sup.1 is taken together with
R.sup.27.
9. A compound of claim 8, wherein R.sup.1 and R.sup.27 taken
together are selected from: a) --CH.sub.2 NR.sup.9 --(C.dbd.O)-- b)
--OCH.sub.2 (C.dbd.O)-- c) --CH.sub.2 CH.sub.2 (C.dbd.O)-- d)
--CH.sub.2 --O(C.dbd.O)-- e) --CH.sub.2 S(C.dbd.O)-- f)
--O(C.dbd.O)-- g) --CH.sub.2 (C.dbd.O)-- h) --NR.sup.9 (C.dbd.O)--
i) --NR.sup.9 (SO.sub.2)-- j) --CH.sub.2 NR.sup.9 SO.sub.2 -- k)
--NR.sup.9 CH.sub.2 (C.dbd.O)-- and l) --SCH.sub.2 (C.dbd.O)--.
10. A compound of claim 9, wherein R.sup.1 and R.sup.27 taken
together are selected from: a) --CH.sub.2 --(C.dbd.O)-- b)
--O(C.dbd.O)-- c) --CH.sub.2 CH.sub.2 -- d) --S(C.dbd.O)-- e)
--N.dbd.N-- f) --NR.sup.9 SO.sub.2 -- g) --N.dbd.CR.sup.9 -- h)
--NR.sup.9 (C.dbd.O)-- and i) --CH.dbd.CH--.
11. A compound of claim 3, wherein R.sup.2 is hydrogen, halogen,
C.sub.1-5 alkoxy, C.sub.1-5 alkyl, cyano, or R.sup.e R.sup.f N,
where R.sup.e and R.sup.f are H or C.sub.1-5 alkyl, or are taken
together to form a 5-7 membered heterocyclic ring.
12. A compound of claim 3, wherein R.sup.3 is hydrogen, halogen,
C.sub.1-5 alkoxy, C.sub.1-5 alkyl, cyano, nitro, or R.sup.g R.sup.h
N, where R.sup.e and R.sup.f are H or C.sub.1-5 alkyl, or are taken
together to form a 5-7 membered heterocyclic ring.
13. A compound of claim 1, wherein R.sup.5 and R.sup.6 are
independently selected from hydrogen and C.sub.1-3 alkyl.
14. A compound of claim 12, wherein one of R.sup.5 and R.sup.6 is
H.
15. A compound of claim 14, wherein R.sup.5 and R.sup.6 are each
H.
16. A compound of claim 1, wherein one of R.sup.7 and R.sup.8 is H
and the other is 5-7 membered carbocyclyl or heterocyclyl.
17. A compound of claim 1, wherein R.sup.7 and R.sup.8 are taken
together to form an optionally substituted 5- to 7-membered
carbocyclic or heterocyclic ring.
18. A compound of claim 16, wherein R.sup.7 and R.sup.8 taken
together form a six-membered heterocyclyl.
19. A compound of claim 16, wherein R.sup.7 and R.sup.8 taken
together form pyridinyl, pyrimidinyl, or piperazinyl, optionally
N-substituted with --(C.dbd.O)R.sup.4, --SO.sub.2 R.sup.4, or
--(C.dbd.O)NHR.sup.4.
20. A compound of claim 3, wherein each of R.sup.a, R.sup.e,
R.sup.m, and R.sup.o is independently selected from hydrogen,
C.sub.1-5 alkyl, C.sub.2-8 acyl, and the respective ROC.dbd.O,
RRNC.dbd.O, RSO, RSO.sub.2, and RRNSO.sub.2 groups.
21. A compound of claim 19, wherein each of R.sup.a, R.sup.e,
R.sup.m, R.sup.o, R.sup.b, R.sup.f, R.sup.n, and R.sup.p is
independently selected from hydrogen and C.sub.1-5 alkyl; or,
independently, R.sup.a and R.sup.b, R.sup.e and R.sup.f, R.sup.m
and R.sup.n, and R.sup.o and R.sup.p, taken together, form an
optionally substituted 4- to 7-membered carbocyclic or heterocyclic
ring.
22. A compound of claim 21, wherein: (1) R.sup.a and R.sup.b taken
together are independently morpholinyl, piperidinyl, or
pyrrolidinyl; (2) R.sup.e and R.sup.f taken together are
morpholinyl, piperidinyl, or pyrrolidinyl; or (3) both (1) and (2)
apply.
23. A compound of claim 3, wherein each of R.sup.c and R.sup.d,
R.sup.i and R.sup.j, R.sup.k and R.sup.l is independently hydrogen
or C.sub.1-5 alkyl, alternatively, R.sup.c and R.sup.d, R.sup.i and
Rj, and R.sup.k and R.sup.l, independently, can be taken together
to form an optionally substituted 4- to 7-membered heterocyclic
ring, which ring may be saturated, unsaturated or aromatic.
24. A compound of claim 23, wherein R.sup.c and R.sup.d, R.sup.i
and R.sup.j, and R.sup.k and R.sup.l, independently, are taken
together to form an optionally substituted 4- to 7-membered
heterocyclic ring, which ring may be saturated, unsaturated or
aromatic.
25. A compound of claim 3, wherein each of R.sup.b, R.sup.f,
R.sup.n, R.sup.p, R.sup.32, R.sup.33, R.sup.34, R.sup.35, R.sup.36,
R.sup.37, R.sup.39, and R.sup.40 is independently H or C.sub.1-5
alkyl.
26. A compound of claim 3, wherein each of R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.19, R.sup.38, and
R.sup.41 is independently H or C.sub.1-5 alkyl.
27. A compound of claim 3, wherein R.sup.g is C.sub.1-5 alkyl,
C.sub.2-8 acyl, R.sup.17 OC.dbd.O, R.sup.17 R.sup.18 NC.dbd.O,
R.sup.16 S, R.sup.16 SO, R.sup.16 SO.sub.2, or R.sup.17 R.sup.18
NSO.sub.2 ; and R.sup.h hydrogen or C.sub.1-5 alkyl; alternatively,
R.sup.g and R.sup.h can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring.
28. A compound of claim 3, wherein R.sup.17 and R.sup.18
independently are hydrogen or C.sub.1-5 alkyl.
29. A compound of claim 1, wherein n is 1.
30. A compound of claim 1, wherein n is 0.
31. A compound of claim 1, wherein G is C.sub.3-4 alkanediyl,
optionally substituted with hydroxy, halogen, (L)-C.sub.1-5
alkyloxy, or [(L)-C.sub.1-5 alkylene]amino.
32. A compound of claim 31, wherein G is C.sub.3 alkanediyl,
optionally substituted with hydroxy, (L)-C.sub.1-5 alkyloxy, or
[(L)-C.sub.1-5 alkylene]amino.
33. A compound of claim 3, wherein each of R.sup.20 and R.sup.21 is
independently selected from hydrogen, halogen, C.sub.1-5 alkoxy,
C.sub.1-5 alkyl, cyano, nitro, and R.sup.m R.sup.n N or R.sup.o
R.sup.p N, respectively.
34. A compound of claim 33, wherein each of R.sup.20 and R.sup.21
is independently selected from hydrogen, halogen, C.sub.1-3 alkyl,
and R.sup.m R.sup.n N or R.sup.o R.sup.p N, respectively.
35. A compound of claim 1, wherein Ar represents a monocyclic ring,
optionally substituted with 1 to 2 substituents selected from
halogen, C.sub.1-5 alkyl, cyano, azido, nitro, R.sup.22 R.sup.23 N,
halomethyl, and halomethoxy.
36. A compound of claim 35, wherein Ar is a six membered ring
substituted with between 1 and 2 substituents independently
selected from methyl, halogen, CF.sub.3, and OCF.sub.3, said
substituent or substituents being at the 4-position, or at the 3-
and 4-positions, respectively.
37. A compound of claim 1, wherein each of R.sup.22, R.sup.23, and
R.sup.24 is hydrogen or C.sub.1-5 alkyl.
38. A compound of claim 1, wherein R.sup.25 and R.sup.26
independently are hydrogen or C.sub.1-5 alkyl; or, alternatively,
R.sup.25 and R.sup.26 can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring.
39. A compound of claim 38, wherein each of R.sup.25 and R.sup.26
is independently hydrogen or C.sub.1-5 alkyl.
40. A compound of claim 1, wherein W is NR.sup.27.
41. A compound of claim 1, wherein W is CHR.sup.28, and R.sup.28 is
hydrogen or C.sub.1-5 alkyl.
42. A compound of claim 1, wherein R.sup.29 is C.sub.1-5 alkyl; or
R.sup.30 and R.sup.31 are independently selected from hydrogen and
C.sub.1-5 alkyl, or R.sup.30 and R.sup.31 are taken together to
form a 5-6 membered heterocyclyl.
43. A compound of claim 3, wherein Ar.sub.2 is formula (e) and
R.sup.1 halogen, C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, cyano,
nitro, and R.sup.a R.sup.b N, or R.sup.1 can be taken together with
R.sup.27 as provided below; R.sup.2 is hydrogen, halogen, C.sub.1-5
alkoxy, C.sub.1-5 alkyl, or R.sup.e R.sup.f N; R.sup.3 is hydrogen,
halogen, C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, cyano, R.sup.g
R.sup.h N; R.sup.5 and R.sup.6 are independently selected from
hydrogen and C.sub.1-3 alkyl; R.sup.7 and R.sup.8 independently are
taken together to form an optionally substituted 5- to 7-membered
carbocyclic or heterocyclic ring, which ring may be saturated,
unsaturated or aromatic; each of R.sup.a, R.sup.e, R.sup.m, and
R.sup.o is independently selected from hydrogen, C.sub.1-5 alkyl,
C.sub.2-8 acyl, and the respective ROC.dbd.O, RRNC.dbd.O, RS, RSO,
RSO.sub.2, and RRNSO.sub.2 groups; each of R.sup.b, R.sup.f,
R.sup.n, and R.sup.p, is independently selected from hydrogen and
C.sub.1-5 alkyl; each of R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.19, and R.sup.38 is independently
C.sub.1-5 alkyl; each of R.sup.c and R.sup.d, R.sup.i and R.sup.j,
R.sup.k and R.sup.l, R.sup.32 and R.sup.33, R.sup.34 and R.sup.35,
R.sup.36 and R.sup.37 are independently are hydrogen or C.sub.1-5
alkyl, or are taken together to form an optionally substituted 4-
to 7-membered heterocyclic ring; R.sup.g is hydrogen, C.sub.1-5
alkyl, C.sub.2-8 acyl, R.sup.17 OC.dbd.O, R.sup.17 R.sup.18
NC.dbd.O, R.sup.16 S, R.sup.16 SO, R.sup.16 SO.sub.2, or R.sup.17
R.sup.18 NSO.sub.2 ; R.sup.h is hydrogen or C.sub.1-5 alkyl;
alternatively, R.sup.g and R.sup.h can be taken together to form an
optionally substituted 4- to 7-membered heterocyclic ring; R.sup.17
and R.sup.18 independently are hydrogen or C.sub.1-5 alkyl; n is 0
or 1; G is C.sub.3-4 alkenediyl or C.sub.3-4 alkanediyl, optionally
substituted with hydroxy, halogen, C.sub.1-5 alkyloxy,
(L)-C.sub.1-5 alkoxy, N.sub.3, or [(L)-C.sub.1-5 alkylene]amino; L
is amino, mono- or di-C.sub.1-5 alkylamino, pyrrolidinyl,
morpholinyl, piperidinyl homopiperidinyl, or piperazinyl, wherein
available ring nitrogens may be optionally substituted with
C.sub.1-5 alkyl, benzyl, C.sub.1-5 alkylcarbonyl, or C.sub.1-5
alkyloxycarbonyl; Y.sub.e is nitrogen or R.sup.20 C; Z.sub.e is
nitrogen or R.sup.21 C; R.sup.20 and R.sup.21 are independently
selected from hydrogen, halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl,
cyano, nitro, and R.sup.m R.sup.n N or R.sup.o R.sup.p N,
respectively; alternatively, R.sup.3 and R.sup.20 or R.sup.3 and
R.sup.21 can be taken together to form an optionally substituted 5-
or 6-membered carbocyclic or heterocyclic ring; Ar represents a
monocyclic or bicyclic aryl or heteroaryl ring, optionally
substituted with between 1 and 3 substituents independently
selected from halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, cyano,
azido, nitro, R.sup.22 R.sup.23 N, R.sup.24 SO.sub.2, R.sup.24
OC.dbd.O, R.sup.25 R.sup.26 NC.dbd.O, CF.sub.3, OCF.sub.3, CF.sub.3
S, and C.sub.1-5 alkylthio; R.sup.22 is hydrogen, C.sub.1-5 alkyl,
phenyl, benzyl, phenethyl, C.sub.1-5 heterocyclyl, C.sub.2-8 acyl,
aroyl, R.sup.24 OC.dbd.O, R.sup.25 R.sup.26 NC.dbd.O, R.sup.24 SO,
R.sup.24 SO.sub.2, or R.sup.25 R.sup.26 NSO.sub.2 ; R.sup.23 is
hydrogen or C.sub.1-5 alkyl; alternatively, R.sup.22 and R.sup.23
can be taken together to form an optionally substituted 4- to
7-membered heterocyclic ring; R.sup.24 is hydrogen or C.sub.1-5
alkyl; R.sup.25 and R.sup.26 are independently hydrogen or
C.sub.1-5 alkyl; or, alternatively, R.sup.25 and R.sup.26 can be
taken together to form an optionally substituted 4- to 7-membered
heterocyclic; W is NR.sup.27 or CHR.sup.28 ; R.sup.27 is hydrogen,
C.sub.1-5 alkyl, R.sup.29 OC.dbd.O, R.sup.30 R.sup.31 NC.dbd.O,
R.sup.29 SO, R.sup.29 SO.sub.2, or R.sup.30 R.sup.31 NSO.sub.2 ;
or, alternatively, R.sup.27 and R.sup.1 can be taken together to
form an optionally substituted 5- or 6-membered heterocyclic ring,
which ring may be saturated, unsaturated or aromatic; R.sup.28 is
hydrogen, hydroxy, C.sub.1-5 heterocyclyl, phenyl, or C.sub.1-5
alkyl; R.sup.29 is C.sub.1-5 alkyl; and R.sup.30 and R.sup.31 are
independently selected from hydrogen, C.sub.1-5 alkyl;
alternatively, R.sup.30 and R.sup.31 can be taken together to form
an optionally substituted 4- to 7-membered heterocyclic.
44. A compound of claim 42, wherein R.sup.1 and R.sup.27 taken
together are selected from: a) --CH.sub.2 NR.sup.9 --(C.dbd.O)-- b)
--OCH.sub.2 (C.dbd.O)-- c) --CH.sub.2 CH.sub.2 (C.dbd.O)-- d)
--CH.sub.2 --O(C.dbd.O)-- e) --CH.sub.2 S(C.dbd.O)-- f)
--O(C.dbd.O)-- g) --CH.sub.2 (C.dbd.O)-- h) --NR.sup.9 (C.dbd.O)--
i) --NR.sup.9 (SO.sub.2)-- j) --CH.sub.2 NR.sup.9 SO.sub.2 -- k)
--NR.sup.9 CH.sub.2 (C.dbd.O)-- and l) --SCH.sub.2 (C.dbd.O)--.
45. A compound of claim 42, wherein R.sup.1 taken together with
R.sub.27 are selected from: a) --CH.sub.2 --(C.dbd.O)-- b)
--O(C.dbd.O)-- c) --CH.sub.2 CH.sub.2 -- d) --S(C.dbd.O)-- e)
--N.dbd.N-- f) --NR.sup.9 SO.sub.2 -- g) --N.dbd.CR.sup.9 -- h)
--NR.sup.9 (C.dbd.O)-- and i) --CH.dbd.CH--.
46. A compound of claim 1, wherein one of R.sup.5 and R.sup.6 is H,
R.sup.7 and R.sup.8 are taken together to form an optionally
substituted 6-membered carbocyclic or heterocyclic ring; and Ar
represents a monocyclic ring, optionally substituted with 1 to 2
substituents selected from halogen, C.sub.1-5 alkyl, cyano, nitro,
R.sup.22 R.sup.23 N, CF.sub.3 and OCF.sub.3.
47. A compound of claim 46, wherein both R.sup.5 and R.sup.6 are
each H, and Ar is a six membered ring substituted with between 1
and 2 substituents independently selected from halogen, methyl,
CF.sub.3, and OCF.sub.3, said substituent or substituents being at
the 4-position, or at the 3- and 4-positions.
48. A compound of claim 47, wherein R.sup.7 and R.sup.8 taken
together form tetrahydropyridinyl, optionally N-substituted with
--(C.dbd.O)R.sup.4, --SO.sub.2 R.sup.4, or
--(C.dbd.O)NHR.sup.4.
49. A compound of claim 5, wherein X.sub.f is C.dbd.O, SO.sub.2, or
CHR.sup.1f, and Y.sub.f is O or NR.sup.2f, where R.sup.2f is H,
C.sub.1-5 alkyl, C.sub.2-5 heterocyclyl, C.sub.1-5 cyanoalkyl, or
(C.sub.1-5 alkoxycarbonyl)C.sub.1-5 alkylene.
50. A compound of claim 49, wherein R.sup.2f is H, C.sub.1-3 alkyl,
or a C.sub.2-5 heterocyclyl.
51. A compound of claim 5, wherein X.sub.f is C.dbd.O, and Y.sub.f
is O, CHR.sup.2f or NR.sup.2f, where R.sup.2f is H, C.sub.1-5
alkyl, C.sub.2-5 heterocyclyl, C.sub.1-5 cyanoalkyl, or (C.sub.1-5
alkoxycarbonyl)C.sub.1-5 alkylene.
52. A compound of claim 51, wherein X.sub.f is C.dbd.O and Y.sub.f
is O.
53. A compound of claim 5, wherein m is 0 and p is 0; m is 0 and p
is 1; or m is 1 and p is 0.
54. A compound of claim 53, wherein p is 0.
55. A compound of claim 1, wherein R.sup.z is H.
56. A compound of claim 1, wherein R.sup.z is OH.
57. A compound of claim 1, wherein R.sup.z is absent.
58. A compound of claim 3, wherein R.sup.20 and R.sup.3 taken
together are a six-membered carbocyclic or heterocyclic ring
optionally substituted with between 1 and 3 substituents
independently selected from halo, C.sub.1-3 alkoxy, di(C.sub.1-3
alkyl)amino, and C.sub.2-5 acyl.
59. A compound of claim 3, wherein each of R.sup.20 and R.sup.3 is
H.
60. A compound of claim 1, selected from:
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2
-one;
3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-pipe
ridin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid amide;
6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-b
enzoimidazol-2-one;
3-(3,4-Dichloro-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1
-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-c
arboxylic acid amide;
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-d
ihydro-benzoimidazol-1-yl]-acetonitrile;
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-d
ihydro-benzoimidazol-1-yl]-acetic acid ethyl ester;
5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-m
ethyl-1,3-dihydro-benzoimidazol-2-one;
1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-
1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idine-5-carboxylic acid amide;
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl
-1,3-dihydro-benzoimidazol-2-one;
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-
imidazo[4,5-b]pyridin-2-one;
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-
imidazo[4,5-b]pyridin-2-one;
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydro-imidazo[4
,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-
c]pyridine-5-carboxylic acid amide;
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-
methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;
5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-p
henyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-
yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;
6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-i
ndol-2-one;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-
1H-quinolin-2-one;
4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-
one;
4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4
]oxazin-3-one; and
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazo
lin-2-one.
61. A compound of claim 1, selected from:
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-d
ihydro-benzoimidazol-1-yl]-acetonitrile; and
4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,
4]oxazin-3-one.
62. A compound of claim 1, selected from:
2-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimid
azol-2-one;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-one;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-
yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-
1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-eth
anone;
(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihy
dro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-morpholin-4-yl-e
thyl)-1,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-b
enzoimidazol-2-one;
[3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro
-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-ben
zoimidazol-1-yl]-acetonitrile;
5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-
dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-on
e;
1-[3-(4-Chloro-3-methyl-phenyl)-1-(3-{4-[3-(4-chloro-phenyl)-[1,2,4]oxadiaz
ol-5-yl]-piperidin-1-yl}-2-hydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-
c]pyridin-5-yl]-ethanone;
1-[1-{2-Hydroxy-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]-
propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-5-yl]-ethanone;
1-[1-{3-[4-(Benzo[d]isoxazol-3-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(
4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-e
thanone;
1-[1-{3-[4-(5-Chloro-benzooxazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-
(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-
ethanone;
1-[1-{3-[4-(Benzothiazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-
trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-eth
anone;
1-[1-{3-[4-(3,5-Dichloro-pyridin-4-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}
-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-y
l]-ethanone;
1-[1-{3-[4-(1H-Benzoimidazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-t
rifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-etha
none;
6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-
benzo[1,4]oxazin-3-one;
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4
-dihydro-1H-quinolin-2-one;
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4
-dihydro-1H-quinazolin-2-one;
1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2.lambda..sup.6
-benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-tr
ifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propa
n-2-ol;
4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-pyrido[3,
2-b][1,4]oxazin-3-one;
5-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3
-dihydro-indol-2-one;
1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-triflu
oromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-
ol;
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzotriazole;
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-sulfonic acid amide;
5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-trifluoromethyl-phenyl)-pyr
azol-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one
;
4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl
]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one;
(S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6
,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl
-1,3-dihydro-benzoimidazol-2-one; and
(S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluorometh
yl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidi
n-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.
63. A compound of claim 1, selected from:
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-octahydro-benzoimidazo
l-2-one;
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-octahydro-benzoimidazol-2-
one; Acetic acid
1-(1-{3-[5-acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl ester;
Methanesulfonic acid
1-(1-{3-[3-(4-bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl
ester;
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-one;
1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(
3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxyli
c acid amide;
1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(
3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxyli
c acid methylamide; Acetic acid
1-(1-{3-[5-acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-
c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl
ester; Methanesulfonic acid
1-(1-{3-[3-(3,4-dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyra
zolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl
ester;
1-[1-{3-[4-(3,5-Dichloro-pyridin-4-ylamino)-piperidin-1-yl]-2-hydroxy-propy
l}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5
-yl]-ethanone;
1-[1-{3-[4-(Benzooxazol-2-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-tri
fluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethano
ne;
1-[1-{3-[4-(Benzooxazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-t
rifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-etha
none; and
1-(4-Benzooxazol-2-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluorome
thyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.
64. A compound of claim 1, selected from:
1-(4-Benzothiazol-2-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluorom
ethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;
1-{3-[4-(5-Methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-
propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyri
dine-5-carboxylic acid amide;
N-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-N-(3-chloro-phenyl)-b
enzamide;
4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-
one;
4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]
oxazin-3-one;
3-(4-Bromo-phenyl)-1-{3-[4-(5-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-y
l)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-car
boxylic acid amide;
4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one;
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-o
ne;
3-(4-Bromo-phenyl)-1-{3-[4-(6-ethanesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]ox
azin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid amide;
4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-on
e;
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]ox
azin-3-one;
1-[1-[3-(4-Benzothiazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-chloro-
3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;
1-[1-[3-(4-Benzothiazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluo
romethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1
H-quinolin-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-
1H-quinolin-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinoli
n-2-one;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1
H-quinazolin-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-
1H-quinazolin-2-one;
1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]p
yridin-1-yl]-3-[4-(6-chloro-2,2-dioxo-3,4-dihydro-2H-2.lambda..sup.6
-2,1,3-benzothiadiazin-1-yl)-piperidin-1-yl]-propan-2-ol;
1-[4-(6-Chloro-2,2-dioxo-2,3-dihydro-2.lambda..sup.6
-2,1,3-benzothiadiazol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-tri
fluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan
-2-ol; 1-[1-{3-[4-(6-Chloro-2,2-dioxo-2,3-dihydro-2.lambda..sup.6
-2,1,3-benzothiadiazol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-triflu
oromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;
4-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-1,4-benzoxazin-3-on
e;
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinoli
n-2-one;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinoli
n-2-one;
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-on
e;
4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-o
ne;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinol
in-2-one;
1-{2-Hydroxy-3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-prop
yl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine
-5-carboxylic acid tert-butyl ester;
1-{2-Hydroxy-3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-p
ropyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
ine-5-carboxylic acid tert-butyl ester;
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-4H-1,4-benzox
azin-3-one; and
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one.
65. A compound of claim 1, selected from:
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one;
1-{3-[4-(2-Oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-3-(4-t
rifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxy
lic acid tert-butyl ester;
1-{3-[4-(3-Oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-3-(
4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carb
oxylic acid tert-butyl ester;
6-Chloro-4-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzox
azin-3-one;
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-chloro-4H-1,4-benzoxazin-3-one
;
4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one;
4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-o
ne;
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-on
e;
1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-o
ne;
1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-
indol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-o
ne;
1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-
indol-2-one;
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3
-dihydro-indol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-
indol-2-one;
5-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-i
ndol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-on
e;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-i
ndol-2-one;
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-pyrido[3,2-b]-1,4-o
xazin-3-one;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dihydro-
4,1-benzoxazepin-2-one;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,4-dihydro-
3,1-benzoxazin-2-one;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzox
azin-2-one;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dihydro-
4,1-benzoxazepin-2-one;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,4-dihydro-
3,1-benzoxazin-2-one;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzox
azin-2-one;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(5-nitro-2,3-dihydro-indo
l-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5
-yl)-ethanone;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(6-nitro-2,3-dihydro-indo
l-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5
-yl)-ethanone;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-methyl-2,3-dihydro-ind
ol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-
5-yl)-ethanone;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-
1H-quinazolin-2-one;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazo
lin-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinaz
olin-2-one;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one
;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1-(3-chloro-phenyl)-3
-methyl-urea;
1-[3-(4-Benzotriazol-1-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(3,4-dichloro
-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester;
1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(
3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxyli
c acid tert-butyl ester;
5-Chloro-1-(1-{3-[3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one;
1-{3-[4-(5-Methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-
propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyri
dine-5-carboxylic acid tert-butyl ester; and
3-(4-Bromo-phenyl)-1-{3-[4-(5-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-y
l)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-car
boxylic acid tert-butyl ester.
66. A compound of claim 1, selected from:
3-(4-Bromo-phenyl)-1-{3-[4-(6-ethanesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]ox
azin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid tert-butyl ester;
1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-1-yl]-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin
-1-yl]-propan-2-ol;
5-Methyl-4-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one;
4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one;
4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-one;
1-{3-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-3-(
4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;
3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1
-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester;
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-p
iperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxy
lic acid tert-butyl ester;
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl
)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carb
oxylic acid tert-butyl ester;
1-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one;
3-(4-Bromo-phenyl)-1-{3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidi
n-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester;
1-(1-{2-Hydroxy-3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one;
4-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one;
1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one;
4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one;
1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one;
4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one;
4-(1-{2-Hydroxy-3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one;
1-(3-(3,4-Difluoro-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-1-yl]
-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
;
1-[1-{3-[4-(5-Bromo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propy
l}-3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5
-yl]-ethanone;
1-(1-{3-[5-Acetyl-3-(3,4-difluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one;
1-[1-{3-[4-(5-Bromo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propy
l}-3-(3,4-difluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-
ethanone;
1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one;
1-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one;
1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one;
1-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenylamino)-piperidin-1-yl]-2-hyd
roxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
N-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-N-(3-chloro-phenyl)-a
cetamide;
1-(4-Benzoimidazol-1-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluoro
methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenylamino)-piperidin-
1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-(3-(4-Chloro-phenyl)-1-{3-[4-(2-fluoro-phenylamino)-piperidin-1-yl]-2-hyd
roxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-phenylamino-piperidin-1-yl)-propyl
]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone;
1-(3-(4-Chloro-phenyl)-1-{3-[4-(4-chloro-phenylamino)-piperidin-1-yl]-2-hyd
roxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-[1-{3-[4-(4-Bromo-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-chl
oro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;
4-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile;
1-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-p-tolylamino-piperidin-1-yl)-propy
l]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone;
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenylamino)-piperidin-
1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(3-methoxy-phenylamino)-piperidin-
1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-(3-(4-Chloro-phenyl)-1-{3-[4-(3,5-dimethoxy-phenylamino)-piperidin-1-yl]-
2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-[1-{3-[4-(5-Chloro-2-methyl-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl
}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethan
one;
1-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenylamino)-piperidin-1-yl]-2-hyd
roxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
[2-(1-{3-[3-(4-Bromo-phenyl)-5-carbamoyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]
pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic
acid methyl ester;
[2-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic
acid methyl ester;
[2-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-
acetic acid methyl ester; and
3-(4-Bromo-phenyl)-1-{3-[4-(5-ethanesulfonyl-2-methoxycarbonylmethoxy-pheny
lamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-
5-carboxylic acid tert-butyl ester.
67. A compound of claim 1, selected from:
2-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic acid
methyl ester;
1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-o-tolyloxy-piperidin-1-yl)-propyl]-
1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone;
1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-phenoxy-piperidin-1-yl)-propyl]-1,4
,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone;
1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-p-tolyloxy-piperidin-1-yl)-propyl]-
1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone;
1-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenoxy)-piperidin-1-yl]
-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-(3-(4-Bromo-phenyl)-1-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-
propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-(3-(4-Bromo-phenyl)-1-{3-[4-(3-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-
propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-(3-(4-Bromo-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydr
oxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-phenoxy-piperidin-1-yl)-p
ropyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone;
3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-p-tolyloxy-piperidin-1-yl)-p
ropyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenoxy)-piper
idin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-
2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3-chloro-phenoxy)-piperidin-1-yl]-
2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
1-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-o-tolyloxy-piperidin-1-yl
)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone;
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-
yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethan
one;
2-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yloxy)-benzonitrile;
2-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yloxy)-benzonitrile;
1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]p
yridin-1-yl]-3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-propan-2-ol;
1-[1-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-triflu
oromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;
1-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-on
e;
1-{1-[3-(5-Acetyl-3-phenyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-
2-hydroxy-propyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimi
dazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimid
azol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimida
zol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethylsulfanyl-phenyl)-4,5,6,7-tetrahydro-p
yrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-b
enzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-methanesulfonyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimid
azol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimida
zol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-b
enzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-isopropyl-1,3-dihyd
ro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-butyl-1,3-dihydro-b
enzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-benzyl-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-fluoro-1,3-dihydro-benzoimidaz
ol-2-one;
3-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-fluoro-2-oxo-2,3-dihydro-1H-be
nzoimidazole-4-carbonitrile;
1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro-1,3-dihydro-benzoimidaz
ol-2-one;
3-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzoimidaz
ole-5-carbonitrile;
1-{2-Hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pr
opyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid amide;
1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one;
3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimid
azol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid methylamide;
3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimid
azol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid ethylamide;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-benzoimida
zol-2-one; and
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methyl-1,3-dihydro-benzoimida
zol-2-one.
68. A compound of claim 1, selected from:
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5,6-dichloro-1,3-dihydro-benzoi
midazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methyl-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5,6-dichloro-1,3-dihy
dro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-morphol
in-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(3-fluoro-4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimida
zol-2-one;
(R)-1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]
pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2
-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-benzoimid
azol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-chloro-1,3-dihydro-benzoimida
zol-2-one;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyrid
in-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-methyl-1,3-dihydro-benzoimida
zol-2-one;
(R)-1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]
pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoi
midazol-2-one;
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-
2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimida
zol-2-one;
(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihy
dro-benzoimidazol-2-one;
(R)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzo
imidazol-2-one;
(R)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihy
dro-benzoimidazol-2-one;
2-{2-[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyr
azolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihyd
ro-benzoimidazol-1-yl]-ethyl}-isoindole-1,3-dione;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-amino-ethyl)-1,3
-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimida
zol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-benzoimidaz
ol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-b
enzoimidazol-2-one;
6-Chloro-1-(1-{3-[3-(4-chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3
-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimid
azol-2-one;
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1-(2-morpholi
n-4-yl-ethyl)-1,3-dihydrobenzoimidazol-2-one;
[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-aceticacid ethyl ester;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2,2,2-trifluoro-et
hyl)-1,3-dihydrobenzoimidazol-2-one;
[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]acetonitrile;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-hydroxy-ethyl)-1
,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-
benzoimidazol-2-one;
1-Ethyl-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4
,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-
dihydro-benzoimidazol-2-one;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3
-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-hydroxy-ethyl)-1
,3-dihydro-benzoimidazol-2-one;
3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4
,5-b]pyridin-2-one;
[3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-acetonitrile;
2-[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-
benzoimidazol-1-yl]-acetamide;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-oxo-tetrahydro-f
uran-3-yl)-1,3-dihydro-benzoimidazol-2-one; and
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-methoxy-ethyl)-1
,3-dihydro-benzoimidazol-2-one.
69. A compound of claim 1, selected from:
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-oxo-butyl)-1,3-d
ihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-diethylamino-eth
yl)-1,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-cyclopropylmethyl-1
,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-methyl-allyl)-1,
3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-
benzoimidazol-2-one;
5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-m
ethyl-1,3-dihydro-benzoimidazol-2-one;
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3
-dihydro-benzoimidazol-2-one;
N-[4-(5-Acetyl-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-pip
eridin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-phe
nyl]-acetamide;
[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-acetic acid;
1-(1-{3-[5-Acetyl-3-(3-bromo-4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimida
zol-2-one;
3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-i
midazo[4,5-b]pyridin-2-one;
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3
-dihydro-imidazo[4,5-b]pyridin-2-one;
1-(1-{3-[5-(1H-imidazole-4-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3
-dihydro-benzoimidazol-2-one;
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carboxylic acid amide;
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carboxylic acid ethylamide;
1-(1-{3-[5-(isoxazole-5-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetr
ahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-di
hydro-benzoimidazol-2-one;
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-sulfonic acid (N-t-butoxycarbonyl)amide;
1-Methyl-3-(1-{3-[5-(5-methyl-isoxazole-3-carbonyl)-3-(4-trifluoromethyl-ph
enyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-y
l)-1,3-dihydro-benzoimidazol-2-one;
3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3
-dihydro-imidazo[4,5-b]pyridin-2-one;
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-i
midazo[4,5-b]pyridin-2-one;
5-Dimethylamino-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5
,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-meth
yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-ethyl-5-methoxy-1,3-dihydro-im
idazo[4,5-b]pyridin-2-one;
1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
;
1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimida
zol-2-one;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-1-ethyl-5-methoxy-1,3-dihydro-imidazo[4,5
-b]pyridin-2-one;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,
5-b]pyridin-2-one;
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carboxylic acid benzyl ester;
5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-p
henyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-
yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carbothioic acid methylamide;
3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-
piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbox
ylic acid phenylamide;
1-(1-{3-[5-Benzoyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one
;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidaz
ol-2-one;
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimida
zol-2-one;
3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-b
enzoimidazol-2-one;
1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-
1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-
c]pyridine-5-carboxylic acid amide;
1-(1-{3-[3-(4-Bromo-phenyl)-5-phenylmethanesulfonyl-4,5,6,7-tetrahydro-pyra
zolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzo
imidazol-2-one;
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzo
imidazol-2-one;
3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-
piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbox
ylic acid amide;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-benzoimidaz
ol-2-one;
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-be
nzoimidazol-2-one;
3-(4-Bromo-phenyl)-1-{3-[4-(6-chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidaz
ol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine
-5-carboxylic acid amide;
3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl-1,3-dihyd
ro-benzoimidazol-2-one; and
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one.
70. A compound of claim 1, selected from:
3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-
piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfon
ic acid t-butoxycarbonyl-amide;
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one;
3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin
-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic
acid t-butoxycarbonyl-amide;
3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin
-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid amide;
(R)-5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phen
yl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)
-1-methyl-1,3-dihydro-benzoimidazol-2-one;
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2
-one;
1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoi
midazol-2-one;
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-1,3-dihydro
-benzoimidazol-2-one;
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,
5-b]pyridin-2-one;
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-
imidazo[4,5-b]pyridin-2-one;
1-{2-Hydroxy-3-[4-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-
1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-
c]pyridine-5-carboxylic acid amide;
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyrid
in-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine
-5-carboxylic acid amide;
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-d
ihydro-imidazo[4,5-b]pyridin-1-yl]-acetonitrile;
3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-pipe
ridin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid methylamide;
3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyrid
in-2-one;
3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4
,5-b]pyridin-2-one;
[3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-ben
zoimidazol-1-yl]-acetic acid ethyl ester;
[3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-acetic acid ethyl ester;
[3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazo
l-1-yl]-acetic acid ethyl ester;
5-Chloro-3-(1-{3-[3-(3,4-dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahy
dro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihyd
ro-benzoimidazol-2-one;
(R)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6
,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl
-1,3-dihydro-benzoimidazol-2-one;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-pyridin-4-
ylmethyl-1,3-dihydro-benzoimidazol-2-one;
(R)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluorometh
yl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidi
n-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-3H-benzooxazol-2-one;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-methyl-3H-benzooxazol-2-one;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzooxazole-
6-carboxylic acid ethyl ester;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-ethanesulfonyl-3H-benzooxazol
-2-one;
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-methyl-3H-benzooxaz
ol-2-one;
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-ben
zooxazole-6-carboxylic acid ethyl ester;
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-3H-benzooxazol-2-one;
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-ethanesulfonyl-3H-b
enzooxazol-2-one;
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-3H-benzooxa
zol-2-one;
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-one;
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-3H-benzooxaz
ol-2-one;
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3H-oxazolo[4
,5-b]pyridin-2-one;
1-[1-[3-(4-Benzooxazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluor
omethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;
1-[1-{2-Hydroxy-3-[4-(6-methyl-benzooxazol-2-yl)-piperidin-1-yl]-propyl}-3-
(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-
ethanone;
1-[1-{3-[4-(Benzothiazol-2-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-tr
ifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethan
one;
1-[1-{2-Hydroxy-3-[4-(5-methyl-benzooxazol-2-yl)-piperidin-1-yl]-propyl}-3-
(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-
ethanone;
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperidin-1-yl]
-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;
3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pr
opyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbaldehyde;
1-[1-[3-(4-Benzo[b]thiophen-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-tri
fluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethano
ne; and
1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-triflu
oromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-
ol.
71. A pharmaceutical composition, comprising a compound of claim 1,
3, 5, 60, or 61 and a pharmaceutically acceptable carrier.
72. A method for treating a subject with a condition mediated by
cathepsin S, said method comprising administering to the subject a
therapeutically effective amount of a pharmaceutical composition
comprising a compound of claim 1, 3, 5, 60, or 61.
73. A method for inhibiting cathepsin S activity in a subject, said
method comprising administering to the subject a therapeutically
effective amount of a pharmaceutical composition comprising a
compound of claim 1, 3, 60 or 61.
74. A method for treating an autoimmune disease, or inhibiting the
progression of an autoimmune disease, in a subject, said method
comprising administering to the subject a therapeutically effective
amount of a pharmaceutical composition comprising a compound of
claim 1, 3, 60, or 61.
75. A method of claim 74, wherein the autoimmune disease is
selected from lupus, rheumatoid arthritis, and asthma.
76. A method of claim 74, wherein the autoimmune disease is
asthma.
77. A method for treating or inhibiting the progression of tissue
transplant rejection in a subject, said method comprising
administering to the subject a therapeutically effective amount of
a pharmaceutical composition comprising a compound of claim 1, 3,
60, or 61.
78. A method of claim 77, wherein said administration occurs after
said subject has undergone a tissue transplant procedure.
79. A method of claim 77, wherein said administration to said
subject occurs before or during a tissue transplant procedure.
Description
FIELD OF THE INVENTION
This invention relates to a series of substituted pyrazoles,
pharmaceutical compositions containing these compounds, and
intermediates used in their manufacture, and methods of using
them.
BACKGROUND OF THE INVENTION
Cathepsin S (EC 3.4.22.27) is a cysteine protease of the papain
family found primarily in lysosomes (Bromme, D.; McGrath, M. E.
High Level Expression and Crystallization of Recombinant Human
Cathepsin S. Protein Science 1996, 5, 789-791).
The role of cathepsin S in the immune response is anticipated by
its tissue distribution: cathepsin S is found primarily in
lymphatic tissues, lymph nodes, the spleen, B lymphocytes, and
macrophages (Kirschke, H. Chapter 211. Cathepsin S. In Handbook of
Proteolytic Enzymes. Barrett, A. J.; Rawlings, N. D.; Woessner, J.
F., Eds. San Diego: Academic Press, 1998. pp. 621-624.). Cathepsin
S inhibitors have been shown in animal models to modulate antigen
presentation and are effective in an animal model of asthma (Riese,
R. J.; Mitchell, R. N.; Villadangos, J. A.; Shi, G.-P.; Palmer, J.
T.; Karp, E. R.; De Sanctis, G. T.; Ploegh, H. L.; Chapman, H. A.
Cathepsin S Activity Regulates Antigen Presentation and Immunity.
J. Clin. Invest. 1998, 101, 2351-2363 and Shi, G.-P.; Villadangos,
J. A.; Dranoff, G.; Small, C.; Gu, L.; Haley, K. J.; Riese, R.;
Ploegh, H. L.; Chapman, H. A. Cathepsin S Required for Normal MHC
Class II Peptide Loading and Germinal Center Development. Immunity
1999, 10, 197-206.).
Mice in which the gene encoding cathepsin S has been knocked out
are less susceptible to collagen-induced arthritis and their immune
systems have an impaired ability to respond to antigens (Nakagawa,
T. Y.; Brissette, W. H.; Lira, P. D.; Griffiths, R. J.; Petrushova,
N.; Stock, J.; McNeish, J. D.; Eastman, S. E.; Howard, E. D.;
Clarke, S. R. M.; Rosloniec, E. F.; Elliott, E. A.; Rudensky, A. Y.
Impaired Invariant Chain Degradation and Antigen Presentation and
Diminished Collagen-Induced Arthritis in Cathepsin S Null Mice.
Immunity 1999, 10, 207-217).
These data demonstrate that compounds that inhibit the proteolytic
activity of human cathepsin S should find utility in the treatment
of chronic autoimmune diseases including, but not limited to,
lupus, rheumatoid arthritis, and asthma; and have potential utility
in modulating the immune response to tissue transplantation.
There are a number of cathepsin S inhibitors reported in the
literature. The most important patents are listed below.
Certain dipeptidyl nitriles are claimed by Novartis as cathepsin S
inhibitors in: Altmann, et. al. WO-99/24460.
Dipeptidyl vinyl sulfones are claimed by Arris (now Axys) as
cysteine protease (including cathepsin S) inhibitors in: Palmer,
et. al. U.S. Pat. No. 5,976,858.
Certain peptidyl sulfonamides are claimed by Arris/Axys as cysteine
protease (including cathepsin S) inhibitors in: Palmer, et. al.
U.S. Pat. No. 5,776,718 (assigned to Arris, now Axys) & Klaus,
et. al. U.S. Pat. No. 6,030,946 (assigned to Axys).
Compounds somewhat similar to those of the present invention are
described in the following references.
Winters, et. al. (Winters, G.; Sala, A.; Barone, D.; Baldoli, E. J.
Med. Chem. 1985, 28, 934-940; Singh, P.; Sharma, R. C. Quant.
Struct.-Act. Relat. 1990, 9, 29-32; Winters, G.; Sala, A.; Barone,
D. in U.S. Pat. No. 4,500,525 (1985)) have described bicyclic
pyrazoles of the type shown below. R never contains a heterocyclic
ring and no protease inhibitor activity is ascribed to these
molecules; they are described as .alpha.1-adrenergic receptor
modulators. ##STR1##
Shutske, et. al. claim the bicylic pyrazoles below. The pyridine
ring is aromatic in their system (Shutske, G. M.; Kapples, K. J.;
Tomer, J. D. U.S. Pat. No. 5,264,576 (1993)). Although reference is
made to R being a linker to a heterocycle, the claims specify only
R=hydrogen. The compounds are referred to as serotonin reuptake
inhibitors. ##STR2##
The compound
2-[4-[4-(3-methyl-5-phenyl-1H-pyrazol-1-yl)butyl]-1-piperazinyl]-pyrimidin
e is known from EP-382637, which describes pyrimidines having
anxiolytic properties. This compound and analogs are further
described in EP-502786 as cardiovascular and central nervous system
agents. Pharmaceutical formulations with such compounds are
disclosed in EP-655248 for use in the treatment of gastric
secreation and as anti-ulcer agents. WO-9721439 describes
medicaments with such compounds for treating obsessive-compulsive
disorders, sleep apnea, sexual dysfunctions, emesis and motion
sickness.
The compounds
5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole
and
5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole
, in particular the hydrochloride salts thereof, are known from
WO-9852940 and CA 122:314528, where these and similar compounds are
described as kinase inhibitors in the former reference and
possessing affinity for benzodiazepine receptors in the latter
reference.
SUMMARY OF THE INVENTION
The present invention concerns compounds which can be represented
by formula (I): ##STR3##
wherein:
Ar.sub.2 is a monocyclic or bicyclic ring system, unsaturated,
saturated or aromatic, optionally fused, optionally including
between 1 and 5 heteroatom ring moieties independently selected
from O, S, N, SO.sub.2, and C.dbd.O; said Ar.sub.2 ring system
being optionally substituted with between 1 and 4 substituents;
R.sup.5 and R.sup.6 are independently selected from hydrogen and
C.sub.1-5 alkyl; R.sup.7 and R.sup.8 are independently hydrogen,
C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.1-5 alkoxy, C.sub.1-5
alkylthio, halogen, or a 4-7 membered carbocyclyl or heterocyclyl;
alternatively, R.sup.7 and R.sup.8 can be taken together to form an
optionally substituted 5- to 7-membered carbocyclic or heterocyclic
ring, which ring may be unsaturated or aromatic, and may be
optionally substituted with between one and three substituents
independently selected from halo, cyano, amino, hydroxy, nitro,
R.sup.4, R.sup.4 O--, R.sup.4 S--, R.sup.4 O(C.sub.1-5 alkylene)--,
R.sup.4 O(C.dbd.O)--, R.sup.4 (C.dbd.O)--, R.sup.4 (C.dbd.S)--,
R.sup.4 (C.dbd.O)O--, R.sup.4 O(C.dbd.O)(C.dbd.O)--, R.sup.4
SO.sub.2, NHR.sup.44 (C.dbd.NH)--, NHR.sup.44 SO.sub.2 --, and
NHR.sup.44 (C.dbd.O)--; R.sup.4 is H, C.sub.1-5 alkyl, C.sub.2-5
alkenyl, C.sub.1-5 heterocyclyl, (C.sub.1-5 heterocyclyl)C.sub.1-6
alkylene, phenyl, benzyl, phenethyl, NH.sub.2, mono- or
di(C.sub.1-6 alkyl)N--, (C.sub.1-6 alkoxy)carbonyl- or R.sup.42
OR.sup.43 --, wherein R.sup.42 is H, C.sub.1-5 alkyl, C.sub.2-5
alkenyl, phenyl, benzyl, phenethyl, C.sub.1-5 heterocyclyl, or
(C.sub.1-5 heterocyclyl)C.sub.1-6 alkylene and R.sup.43 is
C.sub.1-5 alkylene, phenylene, or divalent C.sub.1-5 heterocyclyl;
R.sup.44 is any one of the values for R.sup.4 ; n is 0, 1, or 2; G
is C.sub.3-6 alkenediyl or C.sub.3-6 alkanediyl, optionally
substituted with hydroxy, halogen, C.sub.1-5 alkoxy, C.sub.1-5
alkyl, oxo, hydroximino, CO.sub.2 R.sup.k, R.sup.k R.sup.l N,
R.sup.k R.sup.l NCO.sub.2, (L)-C.sub.1-4 alkylene-, (L)-C.sub.1-5
alkoxy, N.sub.3 or [(L)-C.sub.1-5 alkylene]amino; each of R.sup.k
and R.sup.l is independently hydrogen, C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, phenethyl, or C.sub.1-5 heterocyclyl;
alternatively R.sup.k and R.sup.l, can be taken together to form an
optionally substituted 4- to 7-membered heterocyclic ring, which
ring may be saturated, unsaturated or aromatic; L is amino, mono-
or di-C.sub.1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl
homopiperidinyl, or piperazinyl, wherein available ring nitrogens
may be optionally substituted with C.sub.1-5 alkyl, benzyl,
C.sub.2-5 acyl, C.sub.1-5 alkylsulfonyl, or C.sub.1-5
alkoxycarbonyl; Ar represents a monocyclic or bicyclic aryl or
heteroaryl ring, optionally substituted with between 1 and 3
substituents independently selected from halogen, C.sub.1-5 alkoxy,
C.sub.1-5 alkyl, C.sub.2-5 alkenyl, cyano, azido, nitro, R.sup.22
R.sup.23 N, R.sup.24 SO.sub.2, R.sup.24 S, R.sup.24 SO, R.sup.24
OC.dbd.O, R.sup.22 R.sup.23 NC.dbd.O, C.sub.1-5 haloalkyl,
C.sub.1-5 haloalkoxy, C.sub.1-5 haloalkylthio, and C.sub.1-5
alkylthio; R.sup.22 is hydrogen, C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, phenethyl, benzyl, or C.sub.1-5 heterocyclyl,
C.sub.2-8 acyl, aroyl, R.sup.38 OC.dbd.O, R.sup.25 R.sup.26
NC.dbd.O, R.sup.38 SO, R.sup.38 SO.sub.2, R.sup.38 S, or R.sup.25
R.sup.26 NSO.sub.2 ; R.sup.38 is H, C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, phenethyl, or C.sub.1-5 heterocyclyl;
R.sup.23 is hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl,
benzyl or C.sub.1-5 heterocyclyl; alternatively, R.sup.22 and
R.sup.23 can be taken together to form an optionally substituted 4-
to 7-membered heterocyclic ring, which ring may be saturated,
unsaturated or aromatic; R.sup.24 is C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, or C.sub.1-5 heterocyclyl; R.sup.25 and
R.sup.26 independently are hydrogen, C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, or C.sub.1-5 heterocyclyl; or,
alternatively, R.sup.25 and R.sup.26 can be taken together to form
an optionally substituted 4- to 7-membered heterocyclic ring, which
ring may be saturated, unsaturated or aromatic; W represents O, S,
NR.sup.27, C.dbd.O, (C.dbd.O)NH, NH(C.dbd.O), CHR.sup.28, or a
covalent bond; R.sup.z is H or OH and the dashed line is absent; or
R.sup.z is absent where the dashed line is an sp.sup.2 bond;
R.sup.27 is hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl,
naphthyl, benzyl, phenethyl, C.sub.1-5 heterocyclyl, C.sub.2-8
acyl, aroyl, R.sup.29 OC.dbd.O, R.sup.30 R.sup.31 NC.dbd.O,
R.sup.29 SO, R.sup.29 S, R.sup.29 SO.sub.2, or R.sup.30 R.sup.31
NSO.sub.2 ; or, alternatively, R.sup.27 and part of Ar.sub.2 can be
taken together to form an optionally substituted 5- or 6-membered
heterocyclic ring with optionally 1 to 3 additional heteroatom
moieties in the ring selected from O, NR.sup.9, NR.sup.10, N,
SO.sub.2, C.dbd.O, and S; which ring may be saturated, unsaturated
or aromatic; R.sup.9 and R.sup.10 are independently selected from
H, C.sub.1-3 alkyl, and --CH.sub.2 CO.sub.2 (C.sub.1-4 alkyl);
R.sup.28 is hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, hydroxy,
phenyl, benzyl, C.sub.1-5 heterocyclyl, R.sup.29 O, R.sup.30
R.sup.31 NC.dbd.O, R.sup.29 S, R.sup.29 SO, R.sup.29 SO.sub.2, or
R.sup.30 R.sup.31 NSO.sub.2 ; R.sup.29 is C.sub.1-5 alkyl,
C.sub.3-5 alkenyl, phenyl, benzyl, or C.sub.1-5 heterocyclyl;
R.sup.30 and R.sup.31 are independently selected from hydrogen,
C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl, phenethyl,
naphthyl, and C.sub.1-5 heteroaryl; alternatively, R.sup.30 and
R.sup.31 can be taken together to form an optionally substituted 4-
to 7-membered ring carbocyclic or heterocyclic ring, which ring may
be saturated, unsaturated or aromatic; wherein each of the above
hydrocarbyl or heterocarbyl groups, unless otherwise indicated, and
in addition to any specified substituents, is optionally and
independently substituted with between 1 and 3 substituents
selected from methyl, halomethyl, hydroxymethyl, halo, hydroxy,
amino, nitro, cyano, C.sub.1-5 alkyl, C.sub.1-5 alkoxy, --COOH,
C.sub.2-6 acyl, [di(C.sub.1-4 alkyl)amino]C.sub.2-5 alkylene,
[di(C.sub.1-4 alkyl)amino]C.sub.2-5 alkyl-NH--CO--, and C.sub.1-5
haloalkoxy; or a pharmaceutically acceptable salt, amide, or ester
thereof; or a stereoisomeric form thereof.
One embodiment of the invention is a compound of formula(I),
wherein Ar.sub.2 is selected from 5-7 membered monocyclic rings,
and [5,6], [6,6], [6,5], and [5,5] fused bicyclic ring systems,
said ring or ring system being carbocyclic or heterocyclic,
saturated, unsaturated, or aromatic, optionally substituted with
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl,
nitro, hydroxy, amino, mono- or di-(C.sub.1-6 alkyl)amino,
C.sub.1-4 alkoxy, C.sub.2-4 alkoxycarbonyl, C.sub.2-6 acyl,
C.sub.2-6 acyloxy, C.sub.1-5 alkylsulfonyl, C.sub.1-5
alkoxycarbonylC.sub.1-4 alkoxy, cyano, and mono- or di-(C.sub.1-6
alkyl)carbamoyl.
Another embodiment of the invention is a compound of formula (I),
wherein Ar.sub.2 is selected from 2,5-di(C.sub.1-6
alkyl)aminopyrrolyl and the following 6 formulae: ##STR4##
wherein each dashed line may be an sp.sup.2 bond or absent; X.sub.c
is O, S, or N; and X.sub.d is O or S; R.sup.1 is hydrogen, halogen,
C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, C.sub.2-5 alkenyl,
cyano, nitro, R.sup.a R.sup.b N, C.sub.2-8 acyl, C.sub.1-5
heterocyclyl, (C.sub.1-5 heterocyclyl)C.sub.1-5 alkylene, R.sup.11
S, R.sup.11 SO, R.sup.11 SO.sub.2, R.sup.c OC.dbd.O, R.sup.c
R.sup.d NC.dbd.O, or R.sup.c R.sup.d NSO.sub.2 ; or R.sup.1 can be
taken together with R.sup.27 as provided below; R.sup.2 is
hydrogen, halogen, C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl,
C.sub.2-5 alkenyl, cyano, nitro, R.sup.e R.sup.f N, C.sub.1-5
heterocyclyl, or C.sub.2-8 acyl; R.sup.3 is hydrogen, halogen,
C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, C.sub.2-5 alkenyl,
cyano, nitro, R.sup.g R.sup.h N, C.sub.2-8 acyl, C.sub.1-5
heterocyclyl, R.sup.h OC.dbd.O, R.sup.g R.sup.h NC.dbd.O, or
R.sup.g R.sup.h NSO.sub.2 ; R.sup.a is selected from hydrogen,
C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl, phenethyl,
C.sub.1-5 heterocyclyl, C.sub.2-8 acyl, aroyl, R.sup.j OC.dbd.O,
R.sup.i R.sup.j NC.dbd.O, R.sup.12 SO, R.sup.12 SO.sub.2, R.sup.12
S, and R.sup.i R.sup.j NSO.sub.2 ; R.sup.e is selected from
hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl,
phenethyl, C.sub.1-5 heterocyclyl, C.sub.2-8 acyl, aroyl, R.sup.32
OC.dbd.O, R.sup.32 R.sup.33 NC.dbd.O, R.sup.13 SO, R.sup.13
SO.sub.2, R.sup.13 S, and R.sup.32 R.sup.33 NSO.sub.2 ; R.sup.m is
selected from hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl,
benzyl, phenethyl, C.sub.1-5 heterocyclyl, C.sub.2-8 acyl, aroyl,
R.sup.34 OC.dbd.O, R.sup.34 R.sup.35 NC.dbd.O, R.sup.15 SO,
R.sup.15 SO.sub.2, R.sup.15 S, and R.sup.34 R.sup.35 NSO.sub.2 ;
R.sup.o is selected from hydrogen, C.sub.1-5 alkyl, C.sub.3-5
alkenyl, phenyl, benzyl, phenethyl, C.sub.1-5 heterocyclyl,
C.sub.2-8 acyl, aroyl, R.sup.36 OC.dbd.O, R.sup.36 R.sup.37
NC.dbd.O, R.sup.19 SO, R.sup.19 SO.sub.2, R.sup.19 S, and R.sup.36
R.sup.37 NSO.sub.2 ; each of R.sup.b, R.sup.f, R.sup.n, R.sup.p,
R.sup.32, R.sup.33, R.sup.34, R.sup.35, R.sup.36, R.sup.37,
R.sup.39, and R.sup.40 is independently selected from hydrogen,
C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl, phenethyl, and
C.sub.1-5 heteroaryl; alternatively, R.sup.a and R.sup.b, R.sup.e
and R.sup.f, R.sup.m and R.sup.n, and R.sup.o and R.sup.p,
independently, can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring, which ring may be
saturated, unsaturated or aromatic; each of R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.19, R.sup.38, and
R.sup.41 is independently C.sub.1-5 alkyl, C.sub.3-5 alkenyl,
phenyl, benzyl, phenethyl, or C.sub.1-5 heterocyclyl; each of
R.sup.c and R.sup.d, and R.sup.i and R.sup.j are independently are
hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl,
phenethyl, or C.sub.1-5 heteroaryl; alternatively, R.sup.c and
R.sup.d, and R.sup.i and R.sup.j, independently, can be taken
together to form an optionally substituted 4- to 7-membered
heterocyclic ring, which ring may be saturated, unsaturated or
aromatic; R.sup.g is hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl,
phenyl, benzyl, phenethyl, C.sub.1-5 heterocyclyl, C.sub.2-8 acyl,
aroyl, R.sup.17 OC.dbd.O, R.sup.17 R.sup.18 NC.dbd.O, R.sup.16 S,
R.sup.16 SO, R.sup.16 SO.sub.2, or R.sup.17 R.sup.18 NSO.sub.2 ;
R.sup.h is hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl,
benzyl, phenethyl or C.sub.1-5 heterocyclyl; alternatively, R.sup.g
and R.sup.h can be taken together to form an optionally substituted
4- to 7-membered heterocyclic ring, which ring may be saturated,
unsaturated or aromatic; R.sup.17 and R.sup.18 independently are
hydrogen, C.sub.1-5 alkyl, C.sub.3-5 alkenyl, phenyl, benzyl, or
C.sub.1-5 heterocyclyl;
alternatively, R.sup.17 and R.sup.18 can be taken together to form
an optionally substituted 4- to 7-membered heterocyclic ring, which
ring may be saturated, unsaturated or aromatic; Y.sub.e is nitrogen
or R.sup.20 C; Z.sub.e is nitrogen or R.sup.21 C; R.sup.20 is
hydrogen, halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, C.sub.2-5
alkenyl, cyano, nitro, R.sup.m R.sup.n N, C.sub.2-8 acyl, R.sup.m
OC.dbd.O, R.sup.14 S, R.sup.14 SO or R.sup.14 SO.sub.2 ; R.sup.21
is hydrogen, halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, C.sub.2-5
alkenyl, cyano, nitro, R.sup.o R.sup.p N, C.sub.2-8 acyl, R.sup.16
OC.dbd.O, R.sup.11 S, R.sup.11 SO or R.sup.11 SO.sub.2 ;
alternatively, R.sup.3 and R.sup.20 or R.sup.3 and R.sup.21 can be
taken together to form an optionally substituted 5- or 6-membered
carbocyclic or heterocyclic ring, which ring may be saturated,
unsaturated or aromatic; wherein said ring may be optionally
substituted with halo, di(C.sub.1-5 alkyl)amino, C.sub.2-5 acyl,
and C.sub.1-5 alkoxy; R.sup.27 is hydrogen, C.sub.1-5 alkyl,
C.sub.3-5 alkenyl, phenyl, naphthyl, benzyl, phenethyl, C.sub.1-5
heterocyclyl, C.sub.2-8 acyl, aroyl, R.sup.29 OC.dbd.O, R.sup.30
R.sup.31 NC.dbd.O, R.sup.29 SO, R.sup.29 S, R.sup.29 SO.sub.2, or
R.sup.30 R.sup.31 NSO.sub.2 ; or, alternatively, R.sup.27 and
R.sup.1 can be taken together to form an optionally substituted 5-
or 6-membered heterocyclic ring with optionally 1 to 3 additional
heteroatom moieties in the ring selected from O, NR.sup.9,
NR.sup.10, N, SO.sub.2, C.dbd.O, and S; which ring may be
saturated, unsaturated or aromatic; R.sup.9 and R.sup.10 are
independently selected from H, C.sub.1-3 alkyl, and --CH.sub.2
CO.sub.2 (C.sub.1-4 alkyl); X.sub.f is CHR.sup.1f, .dbd.N--, NH,
C.dbd.O, SO.sub.2, CHSR.sup.1f wherein, in formula (f), R.sup.1f is
hydrogen, halogen, C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl,
C.sub.3-5 alkenyl, cyano, nitro, R.sup.39 R.sup.40 N, C.sub.2-8
acyl, C.sub.1-5 heterocyclyl, (C.sub.1-5 heterocyclyl)C.sub.1-5
alkylene, R.sup.41 S, R.sup.41 SO, R.sup.41 SO.sub.2, R.sup.39
OC.dbd.O, R.sup.39 R.sup.40 NC.dbd.O, R.sup.39 R.sup.40 NSO.sub.2,
R.sup.41 SO.sub.3 -- or R.sup.39 (C.dbd.O)O--; Y.sub.f is CH.sub.2,
CHR.sup.2f, .dbd.CR.sup.2f, O, or NR.sup.2f, wherein R.sup.2f is H,
C.sub.1-7 alkyl, C.sub.3-5 alkenyl, C.sub.2-8 acyl, C.sub.1-5
heterocyclyl, (C.sub.1-5 heterocyclyl)-C.sub.1-5 alkylene, phenyl,
(phenyl)-C.sub.1-5 alkylene, (C.sub.3-7 cycloalkyl)-C.sub.1-5
alkylene, (H.sub.2 NCO)--C.sub.1-5 alkylene, C.sub.1-5 haloalkyl,
C.sub.1-5 cyanoalkyl, (C.sub.1-5 alkoxycarbonyl)C.sub.1-5 alkylene,
and (phenylcarbonyl)NH--; m is 0 or 1; p is 0 or 1; wherein each of
the above hydrocarbyl or heterocarbyl groups, unless otherwise
indicated, and in addition to any specified substituents, is
optionally and independently substituted with between 1 and 3
substituents selected from methyl, halomethyl, hydroxymethyl, halo,
hydroxy, amino, nitro, cyano, C.sub.1-5 alkyl, C.sub.1-5 alkoxy,
--COOH, C.sub.2-6 acyl, [di(C.sub.1-4 alkyl)amino]C.sub.2-5
alkylene, [di(C.sub.1-4 alkyl)amino]C.sub.2-5 alkyl-NH--CO--, and
C.sub.1-5 haloalkoxy.
The disclosed compounds are high-affinity inhibitors of the
proteolytic activity of human cathepsin S. For use in medicine, the
preparation of pharmaceutically acceptable salts of compounds of
formula (I) may be desirable.
Certain compounds of the present invention may have one stereogenic
atom and may exist as two enantiomers. Certain compounds of the
present invention may have two or more stereogenic atoms and may
further exist as diastereomers. It is to be understood by those
skilled in the art that all such stereoisomers and mixtures thereof
in any proportion are encompassed within the scope of the present
invention.
Another aspect of the invention provides pharmaceutical
compositions comprising a compound of formula (I) and a
pharmaceutically acceptable carrier. A further embodiment of the
invention is a process for making a pharmaceutical composition
comprising mixing a disclosed compound as described above, with a
suitable pharmaceutically acceptable carrier.
The invention also contemplates pharmaceutical compositions
comprising more than one compound of formula (I) and compositions
comprising a compound of formula (I) and another pharmaceutically
active agent.
The invention features a method of treating disorders or conditions
mediated by the cathepsin S enzyme, in a subject in need thereof,
comprising administering to the subject a therapeutically effective
amount of any of the compounds or pharmaceutical compositions
described above. If more than one active agent is administered, the
therapeutically effective amount may be a jointly effective amount.
The compounds described herein inhibit the protease activity of
human cathepsin S, an enzyme involved in the immune response. In
preferred embodiments, cathepsin S inhibition is selective. As
such, the disclosed compounds and compositions are useful in the
prevention, inhibition, or treatment of autoimmune diseases such as
lupus, rheumatoid arthritis, and asthma, and for the prevention,
inhibition, or treatment of tissue transplant rejection.
Additional features and advantages of the invention will become
apparent from the detailed description below, including examples,
and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The invention features pyrazole compounds of formula (I), methods
of making them, compositions containing them, and methods of using
them to treat diseases and conditions, including those mediated by
Cathepsin S.
A. Terms
The following terms are defined below and by their usage throughout
this disclosure.
"Alkyl" includes optionally substituted straight chain and branched
hydrocarbons with at least one hydrogen removed to form a radical
group. Alkyl groups include methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl,
sec-pentyl, hexyl, heptyl, octyl, and so on. Alkyl includes
cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl.
"Alkenyl"includes optionally substituted straight chain and
branched hydrocarbon radicals as above with at least one
carbon-carbon double bond (sp.sup.2). Alkenyls include ethenyl (or
vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or
1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls,
hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture
of double bonds and triple bonds, such as 2-penten-4-ynyl, are
grouped as alkynyls herein. Alkenyl includes cycloalkenyl. Cis and
trans or (E) and (Z) forms are included within the invention.
"Alkynyl" includes optionally substituted straight chain and
branched hydrocarbon radicals as above with at least one
carbon-carbon triple bond (sp). Alkynyls include ethynyl,
propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a
mixture of double bonds and triple bonds, such as 2-penten-4-ynyl,
are grouped as alkynyls herein. Alkynyl does not include
cycloalkynyl.
"Alkoxy" includes an optionally substituted straight chain or
branched alkyl group with a terminal oxygen linking the alkyl group
to the rest of the molecule. Alkoxy includes methoxy, ethoxy,
propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
"Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are analogous to
alkoxy, replacing the terminal oxygen atom of alkoxy with,
respectively, NH (or NR), S, and SO.sub.2. Heteroalkyl includes
alkoxy, aminoalkyl, thioalkyl, and so on.
"Aryl" includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl,
and so on, any of which may be optionally substituted. Aryl also
includes arylalkyl groups such as benzyl, phenethyl, and
phenylpropyl. Aryl includes a ring system containing an optionally
substituted 6-membered carbocyclic aromatic ring, said system may
be bicyclic, bridge, and/or fused. The system may include rings
that are aromatic, or partially or completely saturated. Examples
of ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl,
indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl,
isoquinolinyl, and so on.
"Heterocyclyl" includes optionally substituted aromatic and
nonaromatic rings having carbon atoms and at least one heteroatom
(O, S, N) or heteroatom moiety (SO.sub.2, CO, CONH, COO) in the
ring. Unless otherwise indicated, a heterocyclic radical may have a
valence connecting it to the rest of the molecule through a carbon
atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom,
such as N-piperidyl or 1-pyrazolyl. Preferably a monocyclic
heterocyclyl has between 4 and 7 ring atoms, or between 5 and 6
ring atoms; there may be between 1 and 5 heteroatoms or heteroatom
moieties in the ring, and preferably between 1 and 3. A
heterocyclyl may be saturated, unsaturated, aromatic (e.g.,
heteroaryl), nonaromatic, or fused.
Heterocyclyl also includes fused, e.g., bicyclic, rings, such as
those optionally condensed with an optionally substituted
carbocyclic or heterocyclic five- or six-membered aromatic ring.
For example, "heteroaryl" includes an optionally substituted
six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen
atoms condensed with an optionally substituted five- or
six-membered carbocyclic or heterocyclic aromatic ring. Said
heterocyclic five- or six-membered aromatic ring condensed with the
said five- or six-membered aromatic ring may contain 1, 2 or 3
nitrogen atoms where it is a six-membered ring, or 1, 2 or 3
heteroatoms selected from oxygen, nitrogen and sulfur where it is a
five-membered ring.
Examples of heterocyclyls include thiazoylyl, furyl, pyranyl,
isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,
isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl,
furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl,
pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and
morpholinyl. For example, preferred heterocyclyls or heterocyclic
radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl,
cyclohexylimino, cycloheptylimino,and more preferably,
piperidyl.
Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl,
imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,
benzimidazolyl, benzoxazolyl, benzothiazolyl.
"Acyl" refers to a carbonyl moiety attached to either a hydrogen
atom (i.e., a formyl group) or to an optionally substituted alkyl
or alkenyl chain, or heterocyclyl.
"Halo" or "halogen" includes fluoro, chloro, bromo, and iodo, and
preferably chloro or bromo as a substituent.
"Alkanediyl" or "alkylene" represents straight or branched chain
optionally substituted bivalent alkane radicals such as, for
example, methylene, ethylene, propylene, butylene, pentylene or
hexylene.
"Alkenediyl" represents, analogous to the above, straight or
branched chain optionally substituted bivalent alkene radicals such
as, for example, propenylene, butenylene, pentenylene or
hexenylene. In such radicals, the carbon atom linking a nitrogen
preferably should not be unsaturated.
"Aroyl" refers to a carbonyl moiety attached to an optionally
substituted aryl or heteroaryl group, wherein aryl and heteroaryl
have the definitions provided above. In particular, benzoyl is
phenylcarbonyl.
As defined herein, two radicals, together with the atom(s) to which
they are attached may form an optionally substituted 4- to 7-, 5-
to 7-, or a 5- to 6-membered ring carbocyclic or heterocyclic ring,
which ring may be saturated, unsaturated or aromatic. Said rings
may be as defined above in the Summary of the Invention section.
Particular examples of such rings are as follows in the next
section.
"Pharmaceutically acceptable salts, esters, and amides" include
carboxylate salts (e.g., C.sub.1-8 alkyl, cycloalkyl, aryl,
heteroaryl, or non-aromatic heterocyclic) amino acid addition
salts, esters, and amides which are within a reasonable
benefit/risk ratio, pharmacologically effective and suitable for
contact with the tissues of patients without undue toxicity,
irritation, or allergic response. Representative salts include
hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,
oxalate, valerate, oleate, palmitate, stearate, laurate, borate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactiobionate, and laurylsulfonate. These may include alkali metal
and alkali earth cations such as sodium, potassium, calcium, and
magnesium, as well as non-toxic ammonium, quaternary ammonium, and
amine cations such as tetramethyl ammonium, methylamine,
trimethylamine, and ethylamine. See example, S. M. Berge, et al.,
"Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19 which is
incorporated herein by reference. Representative pharmaceutically
acceptable amides of the invention include those derived from
ammonia, primary C.sub.1-6 alkyl amines and secondary di(C.sub.1-6
alkyl)amines. Secondary amines include 5- or 6-membered
heterocyclic or heteroaromatic ring moieties containing at least
one nitrogen atom and optionally between 1 and 2 additional
heteroatoms. Preferred amides are derived from ammonia, C.sub.1-3
alkyl primary amines, and di(C.sub.1-2 alkyl)amines. Representative
pharmaceutically acceptable esters of the invention include
C.sub.1-7 alkyl, C.sub.5-7 cycloalkyl, phenyl, and
phenyl(C.sub.1-6)alkyl esters. Preferred esters include methyl
esters.
"Patient" or "subject" includes mammals such as humans and animals
(dogs, cats, horses, rats, rabbits, mice, non-human primates) in
need of observation, experiment, treatment or prevention in
connection with the relevant disease or condition. Preferably, the
patient or subject is a human.
"Composition" includes a product comprising the specified
ingredients in the specified amounts as well as any product which
results directly or indirectly from combinations of the specified
ingredients in the specified amounts.
"Therapeutically effective amount" or "effective amount" means that
amount of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue system, animal or
human that is being sought by a researcher, veterinarian, medical
doctor or other clinician, which includes alleviation of the
symptoms of the disease or disorder being treated.
Concerning the various radicals in this disclosure and in the
claims, three general remarks are made. The first remark concerns
valency. As with all hydrocarbon radicals, whether saturated,
unsaturated or aromatic, and whether or not cyclic, straight chain,
or branched, and also similarly with all heterocyclic radicals,
each radical includes substituted radicals of that type and
monovalent, bivalent, and multivalent radicals as indicated by the
context of the claims. The context will indicate that the
substituent is an alkylene or hydrocarbon radical with at least two
hydrogen atoms removed (bivalent) or more hydrogen atoms removed
(multivalent). An example of a bivalent radical linking two parts
of the molecule is G in formula (I) which links two rings.
Second, radicals or structure fragments as defined herein are
understood to include substituted radicals or structure fragments.
Hydrocarbyls include monovalent radicals containing carbon and
hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl, and
cycloalkenyl (whether aromatic or unsaturated), as well as
corresponding divalent radicals such as alkylene, alkenylene,
phenylene, and so on. Heterocarbyls include monovalent and divalent
radicals containing carbon, hydrogen, and at least one heteroatom.
Examples of monovalent heterocarbyls include acyl, acyloxy,
alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino,
hydroxyalkyl, and so on.
Using "alkyl" as an example, "alkyl" should be understood to
include substituted alkyl having one or more substitutions, such as
between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents
may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or
different (chlorobenzyl- or aminomethyl-substituted). Examples of
substituted alkyl include haloalkyl (such as fluoromethyl,
chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl,
perfluoromethyl, and 3-iodocyclopentyl), hydroxyalkyl (such as
hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as
aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl),
nitroalkyl, alkylalkyl, and so on. A di(C.sub.1-6 alkyl)amino group
includes independently selected alkyl groups, to form, for example,
methylpropylamino and isopropylmethylamino, in addition
dialkylamino groups having two of the same alkyl group such as
dimethyl amino or diethylamino.
Third, only stable compounds are intended. For example, where there
is an NR'R" group, and R can be an alkenyl group, the double bond
is at least one carbon removed from the nitrogen to avoid enamine
formation. Similarly, where a dashed line is an optional sp.sup.2
bond, if it is absent, the appropriate hydrogen atom(s) is(are)
included.
Preferred substitutions for Ar or Ar.sub.1 include methyl, methoxy,
fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl),
1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoro, chloro, and bromo,
and particularly methyl, bromo, chloro, perfluoromethyl,
perfluoromethoxy, methoxy, and fluoro. Preferred substitution
patterns for Ar or Ar.sub.1 are 4-substituted or 3,4-disubstituted
phenyl.
Compounds of the invention are further described in the next
section.
B. Compounds
The invention features compounds of formula (I) as described in the
Summary section.
Preferred compounds include those wherein: (a) Ar.sub.2 is selected
from formulae (e); (b) Ar.sub.2 is selected from formulae (f); (c)
Ar.sub.2 is selected from formula (a)-(d); (d) R.sup.1 is halogen,
C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, cyano, nitro, R.sup.a
R.sup.b N or is taken together with R.sup.27 ; (e) R.sup.1 is taken
together with R.sup.27 ; (f) R.sup.1 and R.sup.27 taken together
are selected from:
(1) --CH.sub.2 NR.sup.9 --(C.dbd.O)--
(2) OCH.sub.2 (C.dbd.O)--
(3) --CH.sub.2 CH.sub.2 (C.dbd.O)--
(4) --CH.sub.2 --O(C.dbd.O)--
(5) --CH.sub.2 S(C.dbd.O)--
(6) --O(C.dbd.O)--
(7) --CH.sub.2 (C.dbd.O)--
(8) --NR.sup.9 (C.dbd.O)--
(9) --NR.sup.9 (SO.sub.2)--
(10) --CH.sub.2 NR.sup.9 SO.sub.2 --
(11) --NR.sup.9 CH.sub.2 (C.dbd.O)-- and --SCH2(C.dbd.O)-- (g)
R.sup.1 and R.sup.27 taken together are selected from:
a) --CH.sub.2 --(C.dbd.O)--
b) --O(C.dbd.O)--
c) --CH.sub.2 CH.sub.2 --
d) --S(C.dbd.O)--
e) --N.dbd.N--
f) --NR.sup.9 SO.sub.2 --
g) --N.dbd.CR.sup.9 --
h) --NR.sup.9 (C.dbd.O)-- and
i) --CH.dbd.CH--; (h) R.sup.2 is hydrogen, halogen, C.sub.1-5
alkoxy, C.sub.1-5 alkyl, cyano, or R.sup.e R.sup.f N, where R.sup.e
and R.sup.f are H or C.sub.1-5 alkyl, or are taken together to form
a 5-7 membered heterocyclic ring; (i) R.sup.3 is hydrogen, halogen,
C.sub.1-5 alkoxy, C.sub.1-5 alkyl, cyano, nitro, or R.sup.g R.sup.h
N, where R.sup.e and R.sup.f are H or C.sub.1-5 alkyl, or are taken
together to form a 5-7 membered heterocyclic ring; (j) R.sup.5 and
R.sup.6 are independently selected from hydrogen and C.sub.1-3
alkyl; (k) one of R.sup.5 and R.sup.6 is H; (l) R.sup.5 and R.sup.6
are each H; (m) one of R.sup.7 and R.sup.8 is H and the other is
5-7 membered carbocyclyl or heterocyclyl; (n) R.sup.7 and R.sup.8
are taken together to form an optionally substituted 5- to
7-membered carbocyclic or heterocyclic ring; (o) R.sup.7 and
R.sup.8 taken together form a six-membered heterocyclyl; (p)
R.sup.7 and R.sup.8 taken together form pyridinyl, pyrimidinyl, or
piperazinyl, optionally N-substituted with --(C.dbd.O)R.sup.4,
--SO.sub.2 R.sup.4, or --(C.dbd.O)NHR.sup.44 ; (q) each of R.sup.a,
R.sup.e, R.sup.m, and R.sup.o is independently selected from
hydrogen, C.sub.1-5 alkyl, C.sub.2-8 acyl, and the respective
ROC.dbd.O, RRNC.dbd.O, RSO, RSO.sub.2, and RRNSO.sub.2 groups; (r)
each of R.sup.a, R.sup.e, R.sup.m, R.sup.o, R.sup.b, R.sup.f,
R.sup.n, and R.sup.p is independently selected from hydrogen and
C.sub.1-5 alkyl; or, independently, R.sup.a and R.sup.b, R.sup.e
and R.sup.f, R.sup.m and R.sup.n, and R.sup.o and R.sup.p, taken
together, form an optionally substituted 4- to 7-membered
carbocyclic or heterocyclic ring; (s) (1)R.sup.a and R.sup.b taken
together are independently morpholinyl, piperidinyl, or
pyrrolidinyl; (2) R.sup.e and R.sup.f taken together are
morpholinyl, piperidinyl, or pyrrolidinyl; or (3) both (1) and (2)
apply; (t) each of R.sup.c and R.sup.d, R.sup.i and R.sup.j,
R.sup.k and R.sup.l is independently hydrogen or C.sub.1-5 alkyl,
alternatively, R.sup.c and R.sup.d, R.sup.i and R.sup.j, and
R.sup.k and R.sup.l, independently, can be taken together to form
an optionally substituted 4- to 7-membered heterocyclic ring, which
ring may be saturated, unsaturated or aromatic; (u) R.sup.c and
R.sup.d, R.sup.i and R.sup.j, and R.sup.k and R.sup.l,
independently, are taken together to form an optionally substituted
4- to 7-membered heterocyclic ring, which ring may be saturated,
unsaturated or aromatic; (v) each of R.sup.b, R.sup.f, R.sup.n,
R.sup.p, R.sup.32, R.sup.33, R.sup.34, R.sup.35, R.sup.36,
R.sup.37, R.sup.39, and R.sup.40 is independently H or C.sub.1-5
alkyl; (w) each of R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.19, R.sup.38, and R.sup.41 is
independently H or C.sub.1-5 alkyl; (x) R.sup.g is C.sub.1-5 alkyl,
C.sub.2-8 acyl, R.sup.17 OC.dbd.O, R.sup.17 R.sup.18 NC.dbd.O,
R.sup.16 S, R.sup.16 SO, R.sup.16 SO.sub.2, or R.sup.17 R.sup.18
NSO.sub.2 ; and R.sup.h hydrogen or C.sub.1-5 alkyl; alternatively,
R.sup.g and R.sup.h can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring; (y) R.sup.17 and
R.sup.18 independently are hydrogen or C.sub.1-5 alkyl; (z) n is 1;
(aa) n is 0; (bb) G is C.sub.3-4 alkanediyl, optionally substituted
with hydroxy, halogen, (L)-C.sub.1-5 alkyloxy, or [(L)-C.sub.1-5
alkylene]amino; (cc) G is C.sub.3 alkanediyl, optionally
substituted with hydroxy, (L)-C.sub.1-5 alkyloxy, or [(L)-C.sub.1-5
alkylene]amino; (dd) each of R.sup.20 and R.sup.21 is independently
selected from hydrogen, halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl,
cyano, nitro, and R.sup.m R.sup.n N or R.sup.o R.sup.p N,
respectively; (ee) each of R.sup.20 and R.sup.21 is independently
selected from hydrogen, halogen, C.sub.1-3 alkyl, and R.sup.m
R.sup.n N or R.sup.o R.sup.p N, respectively; (ff) Ar represents a
monocyclic ring, optionally substituted with 1 to 2 substituents
selected from halogen, C.sub.1-5 alkyl, cyano, azido, nitro,
R.sup.22 R.sup.23 N, halomethyl, and halomethoxy; (gg) Ar is a six
membered ring substituted with between 1 and 2 substituents
independently selected from methyl, halogen, CF.sub.3, and
OCF.sub.3, said substituent or substituents being at the
4-position, or at the 3- and 4-positions, respectively; (hh) each
of R.sup.22, R.sup.23, and R.sup.24 is hydrogen or C.sub.1-5 alkyl;
(ii) R.sup.25 and R.sup.26 independently are hydrogen or C.sub.1-5
alkyl; or, alternatively, R.sup.25 and R.sup.26 can be taken
together to form an optionally substituted 4- to 7-membered
heterocyclic ring; (jj) each of R.sup.25 and R.sup.26 is
independently hydrogen or C.sub.1-5 alkyl; (kk) W is NR.sup.27 ;
(ll) W is CHR.sup.28, and R.sup.28 is hydrogen or C.sub.1-5 alkyl;
(mm) R.sup.29 is C.sub.1-5 alkyl; or R.sup.30 and R.sup.31 are
independently selected from hydrogen and C.sub.1-5 alkyl, or
R.sup.30 and R.sup.31 are taken together to form a 5-6 membered
heterocyclyl; (nn) Ar.sub.2 is formula (e) and R.sup.1 is halogen,
C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, cyano, nitro, and
R.sup.a R.sup.b N, or R.sup.1 can be taken together with R.sup.27
as provided below; R.sup.2 is hydrogen, halogen, C.sub.1-5 alkoxy,
C.sub.1-5 alkyl, or R.sup.e R.sup.f N; R.sup.3 is hydrogen,
halogen, C.sub.1-5 alkoxy, hydroxy, C.sub.1-5 alkyl, cyano, R.sup.g
R.sup.h N; R.sup.5 and R.sup.6 are independently selected from
hydrogen and C.sub.1-3 alkyl; (oo) R.sup.7 and R.sup.8
independently are taken together to form an optionally substituted
5- to 7-membered carbocyclic or heterocyclic ring, which ring may
be saturated, unsaturated or aromatic; (pp) each of R.sup.a
R.sup.e, R.sup.m, and R.sup.o is independently selected from
hydrogen, C.sub.1-5 alkyl, C.sub.2-8 acyl, and the respective
ROC.dbd.O, RRNC.dbd.O, RS, RSO, RSO.sub.2, and RRNSO.sub.2 groups;
(qq) each of R.sup.b, R.sup.f, R.sup.n, and R.sup.p, is
independently selected from hydrogen and C.sub.1-5 alkyl; each of
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.19, and R.sup.38 is independently C.sub.1-5 alkyl; each of
R.sup.c and R.sup.d, R.sup.i and R.sup.j, R.sup.k and R.sup.l,
R.sup.32 and R.sup.33, R.sup.34 and R.sup.35, R.sup.36 and R.sup.37
are independently are hydrogen or C.sub.1-5 alkyl, or are taken
together to form an optionally substituted 4- to 7-membered
heterocyclic ring; (rr) R.sup.g is hydrogen, C.sub.1-5 alkyl,
C.sub.2-8 acyl, R.sup.17 OC.dbd.O, R.sup.17 R.sup.18 NC.dbd.O,
R.sup.16 S, R.sup.16 SO, R.sup.16 SO.sub.2, or R.sup.17 R.sup.18
NSO.sub.2 ; R.sup.h is hydrogen or C.sub.1-5 alkyl; alternatively,
R.sup.g and R.sup.h can be taken together to form an optionally
substituted 4- to 7-membered heterocyclic ring; R.sup.17 and
R.sup.18 independently are hydrogen or C.sub.1-5 alkyl; n is 0 or
1; (ss) G is C.sub.3-4 alkenediyl or C.sub.3-4 alkanediyl,
optionally substituted with hydroxy, halogen, C.sub.1-5 alkyloxy,
(L)-C.sub.1-5 alkoxy, or [(L)-C.sub.1-5 alkylene]amino; L is amino,
mono- or di-C.sub.1-5 alkylamino, pyrrolidinyl, morpholinyl,
piperidinyl homopiperidinyl, or piperazinyl, wherein available ring
nitrogens may be optionally substituted with C.sub.1-5 alkyl,
benzyl, C.sub.1-5 alkylcarbonyl, or C.sub.1-5 alkyloxycarbonyl;
(tt) Y.sub.e is nitrogen or R.sup.20 C; Z.sub.e is nitrogen or
R.sup.21 C; (uu) R.sup.20 and R.sup.21 are independently selected
from hydrogen, halogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, cyano,
nitro, and R.sup.m R.sup.n N or R.sup.o R.sup.p N, respectively;
alternatively, R.sup.3 and R.sup.20 or R.sup.3 and R.sup.21 can be
taken together to form an optionally substituted 5- or 6-membered
carbocyclic or heterocyclic ring; (vv) Ar represents a monocyclic
or bicyclic aryl or heteroaryl ring, optionally substituted with
between 1 and 3 substituents independently selected from halogen,
C.sub.1-5 alkoxy, C.sub.1-5 alkyl, cyano, azido, nitro, R.sup.22
R.sup.23 N, R.sup.24 SO.sub.2, R.sup.24 OC.dbd.O, R.sup.25 R.sup.26
NC.dbd.O, CF.sub.3, OCF.sub.3, CF.sub.3 S, and C.sub.1-5 alkylthio;
R.sup.22 is hydrogen, C.sub.1-5 alkyl, phenyl, benzyl, phenethyl,
C.sub.1-5 heterocyclyl, C.sub.2-8 acyl, aroyl, R.sup.24 OC.dbd.O,
R.sup.25 R.sup.26 NC.dbd.O, R.sup.24 SO, R.sup.24 SO.sub.2, or
R.sup.25 R.sup.26 NSO.sub.2 ; R.sup.23 is hydrogen or C.sub.1-5
alkyl; (ww) alternatively, R.sup.22 and R.sup.23 can be taken
together to form an optionally substituted 4- to 7-membered
heterocyclic ring; R.sup.24 is hydrogen or C.sub.1-5 alkyl;
R.sup.25 and R.sup.26 are independently hydrogen or C.sub.1-5
alkyl; or, alternatively, R.sup.25 and R.sup.26 can be taken
together to form an optionally substituted 4- to 7-membered
heterocyclic; W is NR.sup.27 or CHR.sup.28 ; R.sup.27 is hydrogen,
C.sub.1-5 alkyl, R.sup.29 OC.dbd.O, R.sup.30 R.sup.31 NC.dbd.O,
R.sup.29 SO, R.sup.29 SO.sub.2, or R.sup.30 R.sup.31 NSO.sub.2 ;
or, alternatively, R.sup.27 and R.sup.1 can be taken together to
form an optionally substituted 5- or 6-membered heterocyclic ring,
which ring may be saturated, unsaturated or aromatic; R.sup.28 is
hydrogen, hydroxy, C.sub.1-5 heterocyclyl, phenyl, or C.sub.1-5
alkyl; R.sup.29 is C.sub.1-5 alkyl; R.sup.30 and R.sup.31 are
independently selected from hydrogen, C.sub.1-5 alkyl;
alternatively, R.sup.30 and R.sup.31 can be taken together to form
an optionally substituted 4- to 7-membered heterocyclic; (xx) one
of R.sup.5 and R.sup.6 is H; R.sup.7 and R.sup.8 are taken together
to form an optionally substituted 6-membered carbocyclic or
heterocyclic ring; and Ar represents a monocyclic ring, optionally
substituted with 1 to 2 substituents selected from halogen,
C.sub.1-5 alkyl, cyano, azido, nitro, R.sup.22 R.sup.23 N, CF.sub.3
and OCF.sub.3 ; (yy) both R.sup.5 and R.sup.6 are each H, and Ar is
a six membered ring substituted with between 1 and 2 substituents
independently selected from halogen, methyl, CF.sub.3, and
OCF.sub.3, said substituent or substituents being at the
4-position, or at the 3- and 4-positions; (zz) a R.sup.7 and
R.sup.8 taken together form tetrahydropyridinyl, optionally
N-substituted with --(C.dbd.O)R.sup.4, --SO.sub.2 R.sup.4, or
--(C.dbd.O)NHR.sup.44 ; (aaa) X.sub.f is C.dbd.O, SO.sub.2, or
CHR.sup.1f, and Y.sub.f is O or NR.sup.2f, where R.sup.2f is H,
C.sub.1-5 alkyl, C.sub.2-5 heterocyclyl, C.sub.1-5 cyanoalkyl, or
(C.sub.1-5 alkoxycarbonyl)C.sub.1-5 alkylene; (bbb) R.sup.2f is H,
C.sub.1-3 alkyl, or a C.sub.2-5 heterocyclyl; (ccc) X.sub.f is
C.dbd.O, and Y.sub.f is O, CHR.sup.2f or NR.sup.2f, where R.sup.2f
is H, C.sub.1-5 alkyl, C.sub.2-5 heterocyclyl, C.sub.1-5
cyanoalkyl, or (C.sub.1-5 alkoxycarbonyl)C.sub.1-5 alkylene; (ddd)
X.sub.f is C.dbd.O and Y.sub.f is O; (eee) m is 0 and p is 0; m is
0 and p is 1; or m is 1 and p is 0; (fff) p is 0; (ggg) R.sup.z is
H; (hhh) R.sup.z is OH; (iii) R.sup.z is absent; (jjj) R.sup.20 and
R.sup.3 taken together are a six-membered carbocyclic or
heterocyclic ring optionally substituted with between 1 and 3
substituents independently selected from halo, C.sub.1-3 alkoxy,
di(C.sub.1-3 alkyl)amino, and C.sub.2-5 acyl; (kkk) each of
R.sup.20 and R.sup.3 is H; and (lll) combinations of the above.
Specific preferred compounds include those in the Examples
provided, such as:
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one;
1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyra
zolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-
2-one;
3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-pip
eridin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxyli
c acid amide;
6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one;
3-(3,4-Dichloro-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-
1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-
carboxylic acid amide;
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7
-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-
dihydro-benzoimidazol-1-yl]-acetonitrile;
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7
-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-
dihydro-benzoimidazol-1-yl]-acetic acid ethyl ester;
5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)
-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-
methyl-1,3-dihydro-benzoimidazol-2-one;
1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin
-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]py
ridine-5-carboxylic acid amide;
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethy
l-1,3-dihydro-benzoimidazol-2-one;
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro
-imidazo[4,5-b]pyridin-2-one;
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro
-imidazo[4,5-b]pyridin-2-one;
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydro-imidazo[
4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3
-c]pyridine-5-carboxylic acid amide;
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1
-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;
5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-
phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4
-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;
6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-
indol-2-one;
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro
-1H-quinolin-2-one;
4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro
-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3
-one;
4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,
4]oxazin-3-one; and
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro
-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinaz
olin-2-one.
Furthermore, preferred compounds include those wherein Ar or
Ar.sub.1 is selected from 4-trifluoromethylphenyl, 4-bromophenyl,
4-chlorophenyl, 4-chloro-3-methylphenyl and 3,4-dichlorophenyl.
More preferred compounds include Examples 37 and 50.
Related Compounds
The invention provides the disclosed compounds and closely related,
pharmaceutically acceptable forms of the disclosed compounds, such
as salts, esters, amides, acids, hydrates or solvated forms
thereof; masked or protected forms; and racemic mixtures, or
enantiomerically or optically pure forms. Related compounds also
include compounds of the invention that have been modified to be
detectable, e.g., isotopically labelled with .sup.18 F for use as a
probe in positron emission tomography (PET) or single-photon
emission computed tomography (SPECT).
The invention also includes disclosed compounds having one or more
functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a
protecting group. See, e.g., Greene and Wuts, Protective Groups in
Organic Synthesis, 3.sup.rd ed., (1999) John Wiley & Sons, NY.
Some of these masked or protected compounds are pharmaceutically
acceptable; others will be useful as intermediates. Synthetic
intermediates and processes disclosed herein, and minor
modifications thereof, are also within the scope of the
invention.
Hydroxyl Protecting Groups
Protection for the hydroxyl group includes methyl ethers,
substituted methyl ethers, substituted ethyl ethers, substitute
benzyl ethers, and silyl ethers.
Substituted Methyl Ethers
Examples of substituted methyl ethers include methyoxymethyl,
methylthiomethyl, t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,
p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,
t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,
2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,
tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,
4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl
S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
Substituted Ethyl Ethers
Examples of substituted ethyl ethers include 1-ethoxyethyl,
1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers
Examples of substituted benzyl ethers include p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxy)phenyldiphenylmethyl,
4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4"-tris(levulinoyloxyphenyl)methyl,
4,4',4"-tris(benzoyloxyphenyl)methyl,
3-(/midazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers
Examples of silyl ethers include trimethylsilyl, triethylsilyl,
triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,
dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,
diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
Esters
In addition to ethers, a hydroxyl group may be protected as an
ester. Examples of esters include formate, benzoylformate, acetate,
chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,
methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,
p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,
4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate,
pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate,
p-phenylbenzoate, 2,4,6-trimethylbenzoate(mesitoate)
Carbonates
Examples of carbonate protecting groups include methyl,
9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl,
2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,
2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl,
p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,
o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate,
4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage
Examples of assisted cleavage include 2-iodobenzoate,
4-azidobutyrate, 4-nitro-4-methylpentanoate,
o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,
2-(methylthiomethoxy)ethyl carbonate,
4-(methylthiomethoxy)butyrate, and
2-(methylthiomethoxymethyl)benzoate.
Miscellaneous Esters
Examples of miscellaneous esters include
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),
o-(methoxycarbonyl)benzoate, p-P-benzoate, .alpha.-naphthoate,
nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate,
N-phenylcarbamate, borate, dimethylphosphinothioyl, and
2,4-dinitrophenylsulfenate.
Sulfonates
Examples of sulfonates include sulfate, methanesulfonate(mesylate),
benzylsulfonate, and tosylate.
Amino Protecting Groups
Protection for the amino group includes carbamates, amides, and
special --NH protective groups.
Examples of carbamates include methyl and ethyl carbamates,
substituted ethyl carbamates, assisted cleavage carbamates,
photolytic cleavage carbamates, urea-type derivatives, and
miscellaneous carbamates.
Carbamates
Examples of methyl and ethyl carbamates include methyl and ethyl,
9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,
9-(2,7-dibromo)fluorenylmethyl,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,
and 4-methoxyphenacyl.
Substituted Ethyl
Examples of substituted ethyl carbamates include
2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl,
1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,
1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,
1-methyl-1-(4-biphenylyl)ethyl,
1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and
4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,
1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,
4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,
benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,
p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,
9-anthrylmethyl and diphenylmethyl.
Assisted Cleavage
Examples of assisted cleavage include 2-methylthioethyl,
2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,
[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,
2,4-dimethylthiophenyl, 2-phosphonioethyl,
2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,
m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,
5-benzisoxazolylmethyl, and
2-(trifluoromethyl)-6-chromonylmethyl.
Photolytic Cleavage
Examples of photolytic cleavage include m-nitrophenyl,
3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,
and phenyl(o-nitrophenyl)methyl.
Urea-Type Derivatives
Examples of urea-type derivatives include
phenothiazinyl-(10)-carbonyl derivative,
N'-p-toluenesulfonylaminocarbonyl, and
N'-phenylaminothiocarbonyl.
Miscellaneous Carbamates
Examples of miscellaneous carbamates include t-amyl, S-benzyl
thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,
cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,
2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,
1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,
2-iodoethyl, isobornyl, isobutyl, isonicotinyl,
p-(p'-methoxyphenylazo)benzyl, 1-methylcyclobutyl,
1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl,
1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,
1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,
2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and
2,4,6-trimethylbenzyl.
Examples of amides include:
Amides
N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,
N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,
N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, N-benzoyl, N-p-phenylbenzoyl.
Assisted Cleavage
N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,
(N'-dithiobenzyloxycarbonylamino)acetyl,
N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,
N-2-methyl-2-(o-nitrophenoxy)propionyl,
N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,
N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine
derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and
4,5-diphenyl-3-oxazolin-2-one.
Cyclic Imide Derivatives
N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,
N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,
5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and
1-substituted 3,5-dinitro-4-pyridonyl.
Special--NH Protection Groups
Examples of special NH protective groups include
N-Alkyl and N-Aryl Amines
N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,
N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),
quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,
N-5-dibenzosuberyl, N-triphenylmethyl,
N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,
N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and
N-2-picolylamine N'-oxide.
Imine Derivatives
N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene,
N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, and
N-(N'N'-dimethylaminomethylene).
Protection for the Carbonyl Group
Acyclic Acetals and Ketals
Examples of acyclic acetals and ketals include dimethyl,
bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and
diacetyl.
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include 1,3-dioxanes,
5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,
5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes,
4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane,
4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane,
4,5-dimethoxymethyl-1,3-dioxolane, O,O'-phenylenedioxy and
1,5-dihydro-3H-2,4-benzodioxepin.
Acyclic Dithio Acetals and Ketals
Examples of acyclic dithio acetals and ketals include
S,S'-dimethyl, S,S'-diethyl, S,S'-dipropyl, S,S'-dibutyl,
S,S'-dipentyl, S,S'-diphenyl, S,S'-dibenzyl and S,S'-diacetyl.
Cyclic Dithio Acetals and Ketals
Examples of cyclic dithio acetals and ketals include 1,3-dithiane,
1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.
Acyclic Monothio Acetals and Ketals
Examples of acyclic monothio acetals and ketals include
O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl and
O-methyl-S-2-(methylthio)ethyl.
Cyclic Monothio Acetals and Ketals
Examples of cyclic monothio acetals and ketals include
1,3-oxathiolanes.
Miscellaneous Derivatives
O-Substituted Cyanohydrins
Examples of O-substituted cyanohydrins include O-acetyl,
O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
Substituted Hydrazones
Examples of substituted hydrazones include N,N-dimethyl and
2,4-dinitrophenyl.
Oxime Derivatives
Examples of oxime derivatives include O-methyl, O-benzyl and
O-phenylthiomethyl.
Imines
Substituted Methylene Derivatives, Cyclic Derivatives
Examples of substituted methylene and cyclic derivatives include
oxazolidines, 1-methyl-2-(1'-hydroxyalkyl)imidazoles,
N,N'-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,
diethylamine adducts, and methylaluminum
bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.
Protection for the Carboxyl Group
Esters
Substituted Methyl Esters
Examples of substituted methyl esters include 9-fluorenylmethyl,
methoxymethyl, methylthiomethyl, tetrahydropyranyl,
tetrahydrofuranyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl,
p-bromophenacyl, .alpha.-methylphenacyl, p-methoxyphenacyl,
carboxamidomethyl, and N-phthalimidomethyl.
2-Substituted Ethyl Esters
Examples of 2-substituted ethyl esters include
2,2,2-trichloroethyl, 2-haloethyl, .omega.-chloroalkyl,
2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,
2-(2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyl,
1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl,
3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl,
.alpha.-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and
benzyl.
Substituted Benzyl Esters
Examples of substituted benzyl esters include triphenylmethyl,
diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,
2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,
2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,
p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,
2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl,
piperonyl, 4-picolyl and p-P-benzyl.
Silyl Esters
Examples of silyl esters include trimethylsilyl, triethylsilyl,
t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl
and di-t-butylmethylsilyl.
Activated Esters
Examples of activated esters include thiols.
Miscellaneous Derivatives
Examples of miscellaneous derivatives include oxazoles,
2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,
5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and
pentaaminocobalt(III) complex.
Stannyl Esters
Examples of stannyl esters include triethylstannyl and
tri-n-butylstannyl.
Amides and Hydrazides
Amides
Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl,
5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl,
N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and
p-P-benzenesulfonamides.
Hydrazides
Examples of hydrazides include N-phenyl and N,N'-diisopropyl
hydrazides.
C. Synthesis
The compounds of the present invention may be prepared by
conventional synthetic organic chemistry and by matrix or
combinatorial methods according to Schemes 1 to 10 below, and
Examples 1 to 31. Those of ordinary skill in the art will be able
to modify and adapt the guidance provided herein to make the
disclosed compounds. ##STR5## ##STR6## ##STR7## ##STR8## ##STR9##
##STR10## ##STR11## ##STR12## ##STR13## ##STR14##
D. Formulation and Administration
The present compounds inhibit the proteolytic activity of human
cathepsin S and therefore are useful as a medicine especially in
methods for treating patients suffering from disorders or
conditions which are modulated or regulated by the inhibition of
cathepsin S activity.
The invention features a method for treating a subject with a
condition mediated by cathepsin S, said method comprising
administering to the subject a therapeutically effective amount of
a pharmaceutical composition comprising a compound of the
invention. The invention also provides a method for inhibiting
cathepsin S activity in a subject, wherein the method comprises
administering to the subject a therapeutically effective amount of
a pharmaceutical composition comprising a compound of the
invention. A third method is a method for treating an autoimmune
disease, or inhibiting the progression of an autoimmune disease, in
a subject, said method comprising administering to the subject a
therapeutically effective amount of a pharmaceutical composition
comprising a disclosed compound. The autoimmune disease can be, for
example, lupus, rheumatoid arthritis, or preferably, asthma. The
invention also provides a method for treating or inhibiting the
progression of tissue transplant rejection in a subject, the method
comprising administering to the subject a therapeutically effective
amount of a pharmaceutical composition comprising a compound of the
invention. The administration step can occur before, during, and/or
after a tissue transplant procedure.
In view of their inhibitory effect on the proteolytic activity of
human cathepsin S the compounds of the present invention may be
formulated into various pharmaceutical forms for administration
purposes. To prepare these pharmaceutical compositions, an
effective amount of a particular compound, in base or acid addition
salt form, as the active ingredient is intimately mixed with a
pharmaceutically acceptable carrier.
A carrier may take a wide variety of forms depending on the form of
preparation desired for administration. These pharmaceutical
compositions are desirably in unitary dosage form suitable,
preferably, for oral administration or parenteral injection. For
example, in preparing the compositions in oral dosage form, any of
the usual pharmaceutical media may be employed. These include
water, glycols, oils, alcohols and the like in the case of oral
liquid preparations such as suspensions, syrups, elixirs and
solutions; or solid carriers such as starches, sugars, kaolin,
lubricants, binders, disintegrating agents and the like in the case
of powders, pills, capsules and tablets. In view of their ease in
administration, tablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are generally employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, to aid
solubility, may be included. Injectable solutions, for example, may
be prepared in which the carrier comprises saline solution, glucose
solution or a mixture of saline and glucose solution. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed. In the
compositions suitable for percutaneous administration, the carrier
optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives
of any nature in minor proportions, which additives do not cause a
significant deleterious effect to the skin. Such additives may
facilitate the administration to the skin and/or may be helpful for
preparing the desired compositions. These compositions may be
administered in various ways, e.g., as a transdermal patch, as a
spot-on, as an ointment. Acid addition salts of the compounds of
formula I, due to their increased water solubility over the
corresponding base form, are more suitable in the preparation of
aqueous compositions.
It is especially advantageous to formulate the aforementioned
pharmaceutical compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
in the specification herein refers to physically discrete units
suitable as unitary dosages, each unit containing a predetermined
quantity of active ingredient calculated to produce the desired
therapeutic effect in association with the required pharmaceutical
carrier. Examples of such dosage unit forms are tablets (including
scored or coated tablets), capsules, pills, powder packets, wafers,
injectable solutions or suspensions, teaspoonfuls, tablespoonfuls
and the like, and segregated multiples thereof.
Pharmaceutically acceptable acid addition salts include the
therapeutically active non-toxic acid addition salt forms which the
disclosed compounds are able to form. The latter can conveniently
be obtained by treating the base form with an appropriate acid.
Appropriate acids comprise, for example, inorganic acids such as
hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric;
nitric; phosphoric and the like acids; or organic acids such as,
for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic,
oxalic, malonic, succinic, maleic, fumaric, malic, tartaric,
citric, methanesulfonic, ethanesulfonic, benzenesulfonic,
p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmoic
and the like acids. The term addition salt also comprises the
solvates which the disclosed componds, as well as the salts
thereof, are able to form. Such solvates are for example hydrates,
alcoholates and the like. Conversely the salt form can be converted
by treatment with alkali into the free base form.
Stereoisomeric form defines all the possible isomeric forms which
the compounds of formula (I) may possess. Unless otherwise
mentioned or indicated, the chemical designation of compounds
denotes the mixture of all possible stereochemically isomeric
forms, said mixtures containing all diastereomers and enantiomers
of the basic molecular structure. More in particular, stereogenic
centers may have the (R)- or (S)-configuration; substituents on
bivalent cyclic saturated radicals may have either the cis- or
trans-configuration. The invention encompasses stereochemically
isomeric forms including diastereoisomers, as well as mixtures
thereof in any proportion of the disclosed compounds. The disclosed
compounds may also exist in their tautomeric forms. Such forms
although not explicitly indicated in the above and following
formulae are intended to be included within the scope of the
present invention.
Those of skill in the treatment of disorders or conditions mediated
by the cathepsin S enzyme could easily determine the effective
daily amount from the test results presented hereinafter and other
information. In general it is contemplated that a therapeutically
effective dose would be from 0.001 mg/kg to 5 mg/kg body weight,
more preferably from 0.01 mg/kg to 0.5 mg/kg body weight. It may be
appropriate to administer the therapeutically effective dose as
two, three, four or more sub-doses at appropriate intervals
throughout the day. Said sub-doses may be formulated as unit dosage
forms, for example, containing 0.05 mg to 250 mg, and in particular
0.5 to 50 mg of active ingredient per unit dosage form. Examples
include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mg dosage
forms. Compounds of the invention may also be prepared in
time-release or subcutaneous or transdermal patch formulations.
Disclosed compound may also be formulated as a spray or other
topical or inhalable formulations.
The exact dosage and frequency of administration depends on the
particular compound of formula (I) used, the particular condition
being treated, the severity of the condition being treated, the
age, weight and general physical condition of the particular
patient as well as other medication the patient may be taking, as
is well known to those skilled in the art. Furthermore, it is
evident that said effective daily amount may be lowered or
increased depending on the response of the treated patient and/or
depending on the evaluation of the physician prescribing the
compounds of the instant invention. The effective daily amount
ranges mentioned herein are therefore only guidelines.
The next section includes detailed information relating to the
preparation, characterization, and use of the disclosed
compounds.
E. EXAMPLES
Example 1
##STR15##
2-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile
A.
1-[3-(4-Chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-eth
anone.
To a stirred solution of 50 g (0.35 mol) of N-acetyl-4-piperidone
and 31 g (0.35 mol) of morpholine in benzene (350 mL) was added a
catalytic amount (.about.0.25 g) of p-toluenesulfonic acid. The
mixture was heated to reflux for 10 h with a Dean-Stark trap. The
solvent was removed under reduced pressure to give a brown oil. The
crude product was diluted with CH.sub.2 Cl.sub.2 (175 mL) and 50.0
mL (0.35 mol) of Et.sub.3 N was added. The mixture was cooled to
0.degree. C. and a solution of 45.0 mL (0.35 mol) of
4-chlorobenzoyl chloride in CH.sub.2 Cl.sub.2 (50 mL) was added
slowly by dropping funnel over 1 h. The mixture was allowed to warm
to room temperature and stirred overnight. The reaction was then
diluted with 1 N HCl (150 mL) and stirred vigorously for 3 h. The
aqueous layer was extracted with CH.sub.2 Cl.sub.2 (3.times.250 mL)
and the combined extracts were dried over Na.sub.2 SO.sub.4 and the
solvent was removed under reduced pressure. The crude oil was
diluted with EtOH (350 mL) and cooled to 0.degree. C. To this
stirred solution was slowly added 33.0 mL (1.06 mol) of hydrazine
and the mixture was allowed to warm to room temperature and stir
overnight during which time a white precipitate formed. The volume
of the reaction was reduced to .about.150 mL and EtOAc (750 mL) was
added to the mixture. The suspension was stirred vigorously for 2 h
and was filtered then washed with EtOAc (2.times.200 mL) and dried
under vacuum to afford 41.4 g (42% over 3 steps) of a pale yellow
solid. TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.3. MS
(electrospray): m/z calculated for C.sub.14 H.sub.14 ClN.sub.3 O
[M+H].sup.+ 276.08, observed 276.0. .sup.1 H NMR (400 MHz,
CDCl.sub.3, a mixture of amide rotamers): 7.65 (d, J=8.4 Hz, 2H),
7.64 (d, J=9.3 Hz, 2H), 7.58 (d, J=10.5 Hz, 2H), 7.55 (d, J=8.5 Hz,
2H), 4.94 (s, 2H), 4.78 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 3.90 (t,
J=5.8 Hz, 2H), 3.02 (t, J=5.8 Hz, 2H), 2.96 (t, J=5.9 Hz, 2H), 2.36
(s, 3H), 2.31 (s, 3H).
B.
1-[3-(4-Chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]
pyridin-5-yl]-ethanone.
To a stirred solution of 1.00 g (3.63 mmol) of
1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-eth
anone and 2.85 mL (36.3 mmol) of epichlorohydrin was added 1.30 g
(3.99 mmol) of solid Cs.sub.2 CO.sub.3. The reaction was stirred
for 48 h and the solvent was removed under reduced pressure. The
residue was then diluted with H.sub.2 O (50 mL) and EtOAc (50 mL).
The layers were separated, and the organic layer was washed with
H.sub.2 O (25 mL) and brine (25 mL), dried over Na.sub.2 SO.sub.4
and the solvent was removed under reduced pressure. Purification by
flash chromatography (silica, 0-15% acetone/CH.sub.2 Cl.sub.2)
afforded 0.72 g (60%) of a white solid. TLC (silica, 5%
MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.5. MS (electrospray): m/z
calculated for C.sub.17 H.sub.18 ClN.sub.3 O.sub.2 [M+H].sup.+,
332.11, observed 332.0. .sup.1 H NMR (400 MHz, CDCl.sub.3, a
mixture of amide rotamers): 7.60 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.4
Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.80 and
4.73 (A and B of AB quartet, J.sub.ab =15.8 Hz, 2H), 4.60 (s, 2H),
4.47 (dd, J=15.3, 2.5 Hz, 1H), 4.42 (dd, J=15.0, 2.7 Hz, 1H), 4.11
(dd, J=5.3, 2.5 Hz, 1H), 4.08 (dd, J=5.1, 3.3 Hz, 1H), 3.99-3.85
(m, 2H), 3.73 (dt, J=5.9, 1.8 Hz, 2H), 3.37 (m, 2H), 2.87-2.80 (m,
3H), 2.80-2.69 (m, 3H), 2.53 (dd, J=4.7, 2.5 Hz, 1H), 2.48 (dd,
J=4.6, 2.6, 1H), 2.19 (s, 3H), 2.15 (s, 3H).
C. 1-{3-(4-Chloro-phenyl)-1-[3-(1,4-dioxa-8-aza-spiro[4.
5]dec-8-yl)-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-
yl}-ethanone.
To a stirred solution of 3.20 g (9.64 mmol) of
1-[3-(4-chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]
pyridin-5-yl]-ethanone and 2.07 g (14.5 mmol) of
1,4-dioxa-8-azaspiro[4.5]decane in CH.sub.2 Cl.sub.2 (65 mL) was
added 1.79 g (2.89 mmol) of Yb(OTf).sub.3.H.sub.2 O. The reaction
was stirred overnight and was then directly purified by flash
chromatography (silica, 0-5% MeOH/CH.sub.2 Cl.sub.2) to afford 3.70
g (81%) of the title compound. TLC (silica, 5% MeOH/CH.sub.2
Cl.sub.2): R.sub.f =0.35. MS (electrospray), m/z calculated for
C.sub.24 H.sub.31 ClN.sub.4 O.sub.4 [M.sup.+ +H], 475.20, observed
475.1.
D.
1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-one.
A suspension of 0.50 g (0.96 mmol) of
1-{3-(4-chloro-phenyl)-1-[3-(1,4-dioxa-8-aza-spiro[4.
5]dec-8-yl)-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-
yl}-ethanone in 1 N HCl (2.0 mL) was heated to 65.degree. C. for 48
h in a sealed vessel. The reaction was allowed to cool to room
temperature and was diluted with CHCl.sub.3 (20 mL) and saturated
NaHCO.sub.3 (20 mL). The aqueous phase was extracted with
CHCl.sub.3 (2.times.10 mL) and the combined organic extracts were
dried over Na.sub.2 SO.sub.4 and the solvent was removed under
reduced pressure. The crude material was then diluted with Ac.sub.2
O (3.0 mL) and was stirred for 48 h. The solvent was removed under
reduced pressure and the crude material was pumped down overnight.
The resulting solid was dissolved in MeOH (5.0 mL) and a catalytic
amount (0.05 g) of K.sub.2 CO.sub.3 was added to the mixture and
stirring was continued overnight. The reaction was then diluted
with H.sub.2 O (20 mL) and CH.sub.2 Cl.sub.2 (20 mL) and the layers
were separated. The aqueous phase was extracted with CH.sub.2
Cl.sub.2 (2.times.10 mL) and the combined organic extracts were
dried over Na.sub.2 SO.sub.4 and the solvent was removed under
reduced pressure. Purification by flash chromatography (silica,
0-10% MeOH/CH.sub.2 Cl.sub.2) afforded 0.29 g (65% over 3 steps) of
a white solid. TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f
=0.35. MS (electrospray); m/z calculated for C.sub.22 H.sub.27
ClN.sub.4 O.sub.3, [M+H].sup.+, 431.18, observed 431.1. .sup.1 H
NMR (400 MHz, CDCl.sub.3, a mixture of amide rotamers): 7.59 (d,
J=8.3 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.37
(d, J=8.5 Hz, 1H), 4.85 and 4.73 (A and B of AB quartet, J.sub.ab
=15.8 Hz, 1H), 4.62 (s, 1H), 4.26-4.12 (m, 2H), 4.09-3.68 (m, 4H),
3.49 (s, 1.5H), 3.28 (s, 1.5H).
E.
2-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]py
ridin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile.
To a stirred solution of 50.0 mg (116.0 .mu.mol) of
5-1-{3-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-one and 9.6 mg (82.5
.mu.mol) of 2-aminobenzonitrile in AcOH (0.5 mL) was added 130.0 mg
(917.0 .mu.mol) Na.sub.2 SO.sub.4 and the reaction was allowed to
stir for 1 h. To this mixture was added 58.0 mg (275.0 .mu.mol)
NaBH(OAc).sub.3 and the reaction was stirred for 48 h. The mixture
was diluted with CH.sub.2 Cl.sub.2 (20 mL) and saturated
NaHCO.sub.3 (20 mL). The aqueous phase was extracted with CH.sub.2
Cl.sub.2 (2.times.10 mL) and the combined organic extracts were
dried over Na.sub.2 SO.sub.4 and the solvent was removed under
reduced pressure. Purification by flash chromatography (silica,
0-5% MeOH/CH.sub.2 Cl.sub.2) afforded 9.0 mg (20%) of a white
solid. TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.2. MS
(electrospray): m/z calculated for C.sub.29 H.sub.33 ClN.sub.6
O.sub.2, [M+H].sup.+, 533.24, observed 533.3. .sup.1 H NMR (400
MHz, CDCl.sub.3, a mixture of amide rotamers): 7.58 (d, J=8.6 Hz,
1H), 7.52 (d, J=8.4 Hz, 1H), 7.43-7.34 (m, 4H), 6.69 (dt, J=7.6,
4.0 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.83 and 4.73 (A and B of AB
quartet, J.sub.ab =15.7 Hz, 1H), 4.61 (s, 1H), 4.44 (d, J=7.3 Hz,
1H), 4.33-4.14 (m, 2H), 4.11-3.84 (m, 2H), 3.83-3.67 (m, 1H),
3.55-3.43 (m, 1H), 3.17-2.94 (m, 1H), 2.93-2.75 (m, 2H), 2.74-2.54
(m, 2H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 2.23-1.53 (m, 9H).
Example 2
##STR16##
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimid
azol-2-one
A.
1-[3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-
5-yl]-ethanone.
A solution of N-acetyl-4-piperidone (2.82 g, 20 mmol), morpholine
(1.93 mL, 22 mmol) and p-toluenesulfonic acid (5 mg) in benzene
(8.5 mL) was refluxed for 8 h in a Dean-Stark apparatus. The
solvent was removed and the residue dissolved in CH.sub.2 Cl.sub.2
(20 mL). Triethylamine (3.1 mL) was added and
p-trifluoromethylbenzoyl chloride (3.27 mL, 22 mmol) in CH.sub.2
Cl.sub.2 (4 mL) was added dropwise into the solution at 0.degree.
C. The reaction mixture was stirred at 25.degree. C. for 24 h and
diluted with aqueous HCl (5%, 25 mL). After stirring for another 30
min, the organic layer was separated, washed with H.sub.2 O (20
mL), dried (Na.sub.2 SO.sub.4), and concentrated. The residue was
dissolved in EtOH (95%, 18 mL) and treated at 0.degree. C. with
hydrazine (2.9 mL, 60 mmol). The mixture was stirred at 25.degree.
C. for 3 h and H.sub.2 O (4 mL) was added. Most of the volatiles
were removed and the residue extracted with CH.sub.2 Cl.sub.2 (50
mL). The organic layer was separated, washed with H.sub.2 O (20
mL), dried over Na.sub.2 SO.sub.4, and concentrated. Column
chromatography (silica, 5% MeOH/CH.sub.2 Cl.sub.2) provided 5.1 g
(83%) of a white powder. TLC (silica, 10% MeOH/CH.sub.2 Cl.sub.2):
R.sub.f =0.30. MS (electrospray): m/z 332.0 ([M+Na].sup.+, C.sub.15
H.sub.14 F.sub.3 N.sub.3 O requires 309.1). .sup.1 H NMR
(CDCl.sub.3, 400 MHz, a mixture of two rotamers): 7.73-7.67 (m,
4H), 4.85 (s, 1.2H), 4.68 (s, 0.8H), 3.96 (t, J=4.5 Hz, 0.8H), 3.78
(t, J=4.5 Hz, 1.2H), 2.89 (t, J=4.5 Hz, 1.2H), 2.83 (t, J=4.5 Hz,
0.8H), 2.23 (s, 1.8H), 2.18 (s, 1.2H).
B.
1-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone.
A solution of
1-[3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-
5-yl]-ethanone(2.4 g, 7.77 mmol) in DMF (15 mL) was treated with
cesium carbonate (5.05 g, 15.5 mmol) and epichlorohydrin (6.1 mL,
77.7 mmol) at 25.degree. C. and stirred for 24 h before it was
diluted with EtOAc (100 mL) and H.sub.2 O (50 mL). The organic
layer was separated, washed with H.sub.2 O (2.times.50 mL), brine
(50 mL), dried over Na.sub.2 SO.sub.4, and concentrated. Column
chromatography (silica, 10% acetone/CH.sub.2 Cl.sub.2) provided
2.30 g (81%) of a white powder. TLC (silica, 10% MeOH/CH.sub.2
Cl.sub.2): R.sub.f =0.35. MS (electrospray): m/z 388.0
([M+Na].sup.+, C.sub.18 H.sub.18 F.sub.3 N.sub.3 O.sub.2 requires
365.1). .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of two
rotamers): 7.77 and 7.63 (AB pattern, J.sub.ab =8.2 Hz, 2H), 7.71
and 7.67 (AB pattern, J.sub.ab =8.4 Hz, 2H), 4.82 and 4.76 (AB
pattern, J.sub.ab =15.5 Hz, 1.2H), 4.58 (s, 0.8H), 4.45-4.35 (m,
1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30
(m, 1H), 2.80-2.67 (m, 3H), 2.48-2.42 (m, 1H), 2.13 (s, 1.3H), 2.08
(s, 1.7H).
C.
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimi
dazol-2-one.
A solution of
1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone (1.17 g, 3.2 mmol) in DMF (10 mL)
was treated with ytterbium(III) triflate (0.4 g, 0.64 mmol) and
4-(2-keto-1-benzimidazolinyl)piperidine (1.04 g, 4.8 mmol) at
25.degree. C. and stirred for 48 h before it was diluted with
CH.sub.2 Cl.sub.2 (100 mL) and H.sub.2 O (50 mL). The organic layer
was separated, washed with H.sub.2 O (2.times.50 mL), dried over
Na.sub.2 SO.sub.4, and concentrated. Flash column chromatography
(silica, 5% MeOH/CH.sub.2 Cl.sub.2) afforded 1.71 g (92%) of a
white powder. TLC (silica, 10% MeOH/CH.sub.2 Cl.sub.2): R.sub.f
=0.25. MS (electrospray): m/z 583.5 ([M+H].sup.+, C.sub.30 H.sub.33
F.sub.3 N.sub.6 O.sub.3 requires 582.3). .sup.1 H NMR (CDCl.sub.3,
400 MHz, a mixture of two rotamers): 9.30 (br s, 0.5H), 9.25 (br s,
0.5H), 7.82 and 7.68 (AB pattern, J.sub.ab =8.2 Hz, 2H), 7.76 and
7.72 (AB pattern, J.sub.ab =8.4 Hz, 2H), 7.25-7.05 (m, 4H), 4.92
and 4.80 (AB pattern, J.sub.ab =15.6 Hz, 1.1H), 4.70 (s, 0.9H),
4.40-3.70 (m, 7H), 3.20-2.82 (m, 4H), 2.60-2.45 (m, 4H), 2.35-2.25
(m, 1H), 2.25 (s, 1.5H), 2.20 (s, 1.5H), 1.90-1.87 (m, 2H).
Example 3
##STR17##
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-one
A.
1-[3-(4-Bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-etha
none.
A flask equipped with a Dean-Stark trap, was charged with
N-acetyl-4-piperidone (100.1 g, 709 mmol), piperidine (68 mL, 779
mmol), pTsOH (3.7 g) and benzene (500 mL). The mixture was heated
to 125.degree. C. After 17 h the mixture was allowed to cool and
divided into two portions. A solution of p-bromobenzoyl chloride
(70.0 g, 319 mmol) in CH.sub.2 Cl.sub.2 (400 mL) was added dropwise
to a 0.degree. C. solution of the enamine (ca. 355 mmol) in
CH.sub.2 Cl.sub.2 (320 mL) over 15 h. The mixture was then allowed
to warm to 23.degree. C. and stirred for an additional 5 h. The
solution was treated with 1 N HCl (500 mL) and stirred vigorously
for 1.5 h. The layers were separated and the aqueous layer was
extracted with CH.sub.2 Cl.sub.2 (2.times.300 mL). The combined
extracts were washed with sat. aqueous NaHCO.sub.3 (300 mL),
H.sub.2 O (300 mL), brine (300 mL), dried over Na.sub.2 SO.sub.4
and concentrated. The residue was dissolved in MeOH (300 mL) and
treated with NH.sub.2 NH.sub.2 (50.0 mL, 1.59 mol). The mixture was
stirred for 17 h before the precipitate formed was collected by
filtration and air dried to give 52 g (50%) of the title compound
which was suitable for use without further purification. TLC
(silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.3. MS
(electrospray): m/z calculated for C.sub.14 H.sub.15.sup.79
BrN.sub.3 O [M+H].sup.+, 320.04. found 320. .sup.1 H NMR (CD.sub.3
OD/CDCl.sub.3, 400 MHz, a mixture of amide rotamers): 7.53 and 7.35
(A and B of AA'BB', J=8.5 Hz, 2H), 7.51 and 7.39 (A and B of
AA'BB', J=8.6 Hz, 2H), 4.72 (s, 2H), 4.58 (s, 2H), 3.85 (t, J=5.9
Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 2.81, (t, J=5.8 Hz, 2H), 2.74, (t,
J=5.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
B.
1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]p
yridin-5-yl]-ethanone.
Cs.sub.2 CO.sub.3 (11.58 g, 35.5 mmol) was added to a solution of
1-[3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-etha
none (7.59 g, 23.7 mmol) and epichlorohydrin (20 mL, 234 mmol) in
DMF (100 mL). The mixture was stirred for 18 h then diluted with
EtOAc (800 mL) and washed with saturated aqueous NaHCO.sub.3
(2.times.100 mL), H.sub.2 O (2.times.100 mL), and brine (100 mL).
The NaHCO.sub.3 layer was extracted with EtOAc (2.times.150 mL).
The combined washes were extracted with EtOAc (2.times.100 mL). The
combined extracts were dried over Na.sub.2 SO.sub.4 and
concentrated. Column chromatography (silica, 10-20%
acetone/CH.sub.2 Cl.sub.2) afforded 4.98 g (56%) of the title
compound. HPLC, t.sub.R =4.90 min. (Reverse phase conditions: HP
1100 LCMS, Phenomenex luna 2.1.times.150 mm column, 60%
MeOH/H.sub.2 O (0.5% AcOH) to 90% MeOH/H.sub.2 O (0.5% AcOH), held
at initial conditions for 2 min then ramped to final conditions
over 5 min.) MS (electrospray): m/z calculated for C.sub.17
H.sub.19.sup.79 BrN.sub.3 O.sub.2, [M+H].sup.+, 376.07. found
376.0. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of amide
rotamers): 7.47 (d with fine splittings, J=8.5, Hz, 2H), 7.44 (m,
4H), 7.38 (d with fine splittings, J=8.5, Hz, 2H), 4.71 and 4.64 (A
and B of AB quartet, J.sub.ab =15.7 Hz, 2H), 4.51 (s, 2H), 4.39
(dd, J=15.1, 2.5 Hz, 1H), 4.34 (dd, J=15.0, 2.9 Hz, 1H), 4.02 (dd,
J=5.2, 3.9 Hz, 1H), 3.98 (dd, J=5.3, 3.7 Hz, 1H), 3.83 (m, 2H),
3.64 (m, 2H), 3.25 (br m, 2H), 2.80-2.60 (m, 6H), 2.46 (dd, J=4.6,
2.6 Hz, 1H), 2.38 (dd, J=4.6, 2.6 Hz, 1H), 2.10 (s, 3H), 2.06 (s,
3H).
C. 4-(2-Oxo-benzooxazol-3-yl)-piperidine-1-carboxylic acid
tert-butyl ester.
To a stirred solution of 1.00 g (5.01 mmol) of tert-butyl
4-oxo-1-piperidinecarboxylate and 0.55 g (5.01 mmol) of
2-aminophenol in CH.sub.2 Cl.sub.2 (15 mL) under nitrogen at rt was
added 1.62 g (7.52 mmol) of NaBH(OAc).sub.3 in one portion and the
mixture was stirred for 14 h. The mixture was diluted with CH.sub.2
Cl.sub.2 (50 mL) and saturated NaHCO.sub.3 (75 mL) and the layers
were separated. The aqueous layer was extracted with CH.sub.2
Cl.sub.2 (2.times.25 mL) and the combined organic layers were
washed with brine, dried over Na.sub.2 SO.sub.4, and the solvent
was removed under reduced pressure. The crude solid was diluted
with CH.sub.2 Cl.sub.2 (15 mL) and 0.89 g (5.51 mmol) of
carbonyidiimidazole was added in one portion and mixture was
stirred for 16 h. The mixture was diluted with CH.sub.2 Cl.sub.2
(50 mL) and 1 N HCl (50 mL) and the layers were separated. The
aqueous layer was extracted with CH.sub.2 Cl.sub.2 (2.times.25 mL)
and the combined organic layers were washed with brine, dried over
Na.sub.2 SO.sub.4, and the solvent was removed under reduced
pressure. Flash chromatography (silica, 0-5% acetone/CH.sub.2
Cl.sub.2) afforded 1.59 g (99%) of a white solid. TLC (silica, 5%
acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.6. MS (electrospray): m/z
calculated for C.sub.17 H.sub.22 N.sub.2 O.sub.4, [M+Na].sup.+,
341.1, observed 341.1.
D. 3-Piperidin-4-yl-3H-benzooxazol-2-one.
To a stirred solution of 1.00 g (2.87 mmol) of
4-(2-oxo-benzooxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl
ester in CH.sub.2 Cl.sub.2 (6.0 mL) was added TFA (6.0 mL) and the
mixture was stirred for 12 h. The solvents were removed under
reduced pressure and the crude solid was diluted in MeOH (10 mL)
and saturated NaHCO.sub.3 (15 mL) was added to the mixture and
stirring was continued for 10 min. The solution was diluted with
CH.sub.2 Cl.sub.2 (30 mL) and the layers were separated. The
aqueous phase was extracted with CH.sub.2 Cl.sub.2 (2.times.20 mL)
and the organic layers were combined, dried over Na.sub.2 SO.sub.4
and the solvent was removed under reduced pressure to afford 1.02 g
(88%) of a pale yellow solid. TLC (silica, 10% MeOH/CH.sub.2
Cl.sub.2): R.sub.f =0.1. MS (electrospray): m/z calculated for
C.sub.12 H.sub.14 N.sub.2 O.sub.2, [M+H].sup.+, 219.11, observed
219.1.
E.
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-one.
To a stirred mixture of 0.025 g (0.066 mmol) of
3-piperidin-4-yl-3H-benzooxazol-2-one and 0.015 g (0.066 mmol) of
1-[3-(4-bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]p
yridin-5-yl]-ethanone in EtOH (0.5 mL) was added 0.01 mL (0.066
mmol) of Et.sub.3 N. The mixture was heated to 80.degree. C. in a
sealed vessel for 16 h. The reaction was cooled and the solvent was
removed under reduced pressure. Flash chromatography (silica, 0-5%
MeOH/CH.sub.2 Cl.sub.2) afforded 0.030 g (79%) of a white foam. TLC
(silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.4. MS
(electrospray): m/z calculated for C.sub.29 H.sub.32 BrN.sub.5
O.sub.4, [M+H].sup.+, 594.16, observed 594.2. .sup.1 H NMR (400
MHz, CDCl.sub.3, a mixture of amide rotamers): 7.60-7.43 (m, 4H),
7.23-7.06 (m, 4H), 4.83 and 4.73 (A and B of AB quartet, J.sub.ab
=15.4 Hz, 1H), 4.61 (s, 1H), 4.38-3.66 (m, 7H), 3.37-3.02 (m, 2H),
2.99-2.28 (m, 6H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 1.99-1.83 (m,
3H).
Example 4
##STR18##
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-
yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
A.
1-[3-(4-Chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-
5-yl]-ethanone.
To a stirred solution of 1-acetyl-4-piperidone (3 g, 0.021 mol) and
morpholine (1.86 g, 0.21 mol) in benzene (21 mL) was added a
catalytic amount (.about.0.015 g) of p-toluenesulfonic acid. The
mixture was heated to reflux for 10 h under a Dean-Stark trap. The
solvent was removed under reduced pressure to give a brown oil. The
crude product was diluted with CH.sub.2 Cl.sub.2 (10.5 mL), and
Et.sub.3 N (3.0 mL, 0.021 mol) was added. The mixture was cooled to
0.degree. C., and a solution of 3-methyl-4-chlorobenzoyl chloride
(2.7 mL, 0.021 mol) in CH.sub.2 Cl.sub.2 (3.0 mL) was added slowly
by dropping funnel over 1 h. The mixture was allowed to warm to
room temperature and stir overnight. The reaction mixture was then
diluted with 1 N HCl (9.0 mL) and stirred vigorously for 3 h. The
aqueous layer was extracted with CH.sub.2 Cl.sub.2 (3.times.15 mL).
The combined extracts were dried over Na.sub.2 SO.sub.4, and the
solvent was removed under reduced pressure. The crude oil was
diluted with EtOH (21 mL) and cooled to 0.degree. C. To this
stirred solution was slowly added hydrazine (2.0 mL, 0.064 mol),
and the mixture was allowed to warm to room temperature and stir
overnight, during which time a white precipitate formed. The volume
of the reaction mixture was reduced to .about.9 mL, and EtOAc (45
mL) was added. The suspension was stirred vigorously for 2 h and
was filtered then washed with EtOAc (2.times.12 mL) and dried under
vacuum to afford 4.93 g (81% over 3 steps) of a pale yellow solid.
TLC (silica, 10% acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.2. MS
(electrospray): exact mass calculated for C.sub.15 H.sub.16
ClN.sub.3 O, 289.10. m/z found, 290.1 [M.sup.+ +H].
B.
1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone.
Cs.sub.2 CO.sub.3 (11 g, 33.8 mmol) was added to a solution of
1-[3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-
5-yl]-ethanone (4.9 g, 16.9 mmol) in DMF (49 mL), which was then
stirred for 15 min. Epichlorohydrin (13.2 mL, 169 mmol) was added,
and the mixture was stirred under N.sub.2 at room temperature for
16 h. EtOAc (250 mL) was added to the reaction mixture, which was
then stirred for 5 min. The resulting solution was washed with
water (2.times.50 mL) and brine (1.times.50 mL). The organic
extracts were dried over Na.sub.2 SO.sub.4 and concentrated. The
residue was purified by column chromatography (silica, 10-20%
acetone/CH.sub.2 Cl.sub.2) to obtain 3.8 g (65%) of a white solid.
TLC (silica, 10% acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.3. MS
(electrospray): exact mass calculated for C.sub.18 H.sub.20
ClN.sub.3 O.sub.2, 345.12. m/z found, 346.1 [M.sup.+ +H], 368.0
[M.sup.+ +Na],
C. 4-(3,4-Dichlorophenoxy)-piperidinium trifluoroacetate.
A suspension of 0.69 g (20.0 mmol) of triphenylphosphine (polymer
supported, 3 mmol P/g) in CH.sub.2 Cl.sub.2 (4.0 mL) was stirred
for 15 min to swell the resin. To this suspension was added 0.20 g
(1.00 mmol) of 1-tert-butoxycarbonyl-4-piperidinol, 0.16 g (1.00
mmol) of 3,4-dichlorophenol, and 0.35 g (1.50 mmol) of
di-tert-butyl azodicarboxylate. The reaction was stirred for 4 h
and was filtered and the resin was washed with 5% MeOH/CH.sub.2
Cl.sub.2 (2.times.20 mL) and Et.sub.2 O (20 mL). The organic layers
were combined and the solvent was removed. The crude oil was
diluted with CH.sub.2 Cl.sub.2 (2.0 mL) and TFA (2.0 mL) and the
mixture was stirred overnight. The solvent was removed under
reduced pressure to afford the crude TFA salt which was used
without further purification. TLC (silica, 10% MeOH/CH.sub.2
Cl.sub.2): R.sub.f =0.1. MS (electrospray): m/z calculated for
C.sub.11 H.sub.13 Cl.sub.2 NO, [M+H].sup.+, 246.04, observed
246.1.
D.
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1
-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone.
To a stirred solution of 25.0 mg (0.066 mmol) of
1-[3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone and 25.0 mg (0.10 mmol) of
4-(3,4-dichlorophenoxy)-piperidinium trifluoroacetate in EtOH (0.5
mL) was added 0.019 mL (0.014 mmol) of Et.sub.3 N. The mixture was
heated to 80.degree. C. in a sealed vessel for 16 h. The reaction
was cooled and the solvent was removed under reduced pressure.
Flash chromatography (0-5% MeOH/CH.sub.2 Cl.sub.2) afforded 28 mg
(74%) of a pale yellow foam. TLC (silica, 5% MeOH/CH.sub.2
Cl.sub.2): R.sub.f =0.5. MS (electrospray): m/z calculated for
C.sub.29 H.sub.33 Cl.sub.3 N.sub.4 O.sub.3, [M+H].sup.+, 591.16,
observed 591.2. .sup.1 H NMR (400 MHz, CDCl.sub.3, a mixture of
amide rotamers): 7.51 (d, J=6.9 Hz, 1H), 7.41-7.29 (m, 3H), 6.99
(d, J=2.9 Hz, 1H), 6.74 (dd, J=9.0, 3.1 Hz, 1H), 4.82 and 4.73 (A
and B of AB quartet, J.sub.ab =15.7 Hz, 1H), 4.60 (s, 1H),
4.46-3.93 (m, 4H), 3.92-3.83 (m, 1H), 3.82-3.68 (m, 1H), 3.08-2.51
(m, 6H), 2.43 (s, 1.5H), 2.41 (s, 1.5H), 2.21 (s, 1.5H), 2.15 (s,
1.5H) 2.00-1.83 (m, 3H), 1.75-1.39 (m, 4H).
Example 5
##STR19##
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-
1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-eth
anone
A. 1-Piperidin-4-yl-2,3-dihydro-1H-indole.
Indoline (11.0 g, 92 mmol) and N-BOC-4-piperidone (18.4 g, 92 mmol)
were set stirring in 300 mL of CH.sub.2 Cl.sub.2 under an
atmosphere of nitrogen at rt. Acetic acid (5.5 mL, 96 mmol) was
then added. After 1.5 h sodium triacetoxyborohydride (27.4 g, 129
mmol) was added and the mixture was left stirring for 4 days. The
mixture was quenched by the slow addition of saturated NaHCO.sub.3.
The organics were separated, dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure to give 28 g (100%) of a clear
dark green liquid. The crude material was brought up in 1:1
TFA/CH.sub.2 Cl.sub.2 (100 mL) and stirred at room temperature.
After 45 min the solvent was evaporated under reduced pressure, the
oil brought up in EtOAc, and cooled on ice to form a beige
precipitate. The solid was filtered, washed with Et.sub.2 O and air
dried to give 22.5 g (57%) of a white solid as a TFA salt. MS
(electrospray): exact mass calculated for C.sub.13 H.sub.18
N.sub.2, 202.15. m/z found, 203.2. .sup.1 H NMR (400 MHz,
DMSO-d.sub.6): 8.74 (br s, 1H), 8.46 (br s, 1H), 7.07 (m, 2H), 6.63
(m, 2H), 3.81 (br s, 1H), 3.46 (m, 2H), 3.37 (m, 2H), 3.12 (m, 2H),
2.95 (m, 2H), 1.86 (m, 4H).
B.
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin
-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-et
hanone.
1-Piperidin-4-yl-2,3-dihydro-1H-indole (TFA salt) (506 mg, 1.18
mmol) and
1-[3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone (261 mg, 0.75 mmol) were set
stirring in 20 mL of EtOH and heated to 80.degree. C. After 20 h
the mixture was cooled, evaporated, brought up in EtOAc and washed
with saturated NaHCO.sub.3. The organics were dried (MgSO.sub.4)
and evaporated to give a clear golden oil. Flash chromatography
(silica, 100% acetone) gave 260 mg (63%) of a white solid. TLC
(silica, 100% acetone): R.sub.f =0.10. MS (electrospray): exact
mass calculated for C.sub.31 H.sub.28 ClN.sub.5 O.sub.2, 547.27.
m/z found, 548.3. .sup.1 H NMR 400 MHz,CDCl.sub.3): 7.64 (m, 1H),
7.43 (m, 2H), 7.16 (m, 2H), 6.72 (s, 1H), 6.50 (m, 1H), 4.88 (m,
1H), 4.73 (s, 1H), 4.28 (m, 2H), 4.13 (m, 2H), 3.92 (m, 2H), 3.47
(m, 3H), 30.9 (m, 6H), 2.55 (m, 6H), 2.27 (m, 3H), 1.84 (m,
4H).
Example 6
##STR20##
(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihy
dro-benzoimidazol-2-one
A.
(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetra
hydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.
A solution of KHMDS (0.5 M, 8.4 mL, 4.1 mmol) was added to a
solution of
1-[3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-
5-yl]-ethanone (1.01 g, 3.49 mmol) in DMF (8.5 mL). The mixture was
stirred for 1 h then (2R)-1-tert-butyldimethylsilylglycidol (1.97
g, 10.5 mmol) was added. The mixture was stirred for 17 h then
partitioned between EtOAc (500 mL) and saturated aqueous
NaHCO.sub.3 (100 mL). The EtOAc layer was washed with H.sub.2 O
(3.times.100 mL), and brine (100 mL). The combined washes were
extracted with EtOAc (2.times.100 mL). The combined extracts were
dried over Na.sub.2 SO.sub.4 and concentrated. The residue was
dissolved in MeOH (50 mL) and treated with CSA (171 mg). The
resulting mixture was stirred for 24 h then concentrated to near
dryness. The residue was diluted with EtOAc (300 mL), washed with
NaHCO.sub.3 (100 mL), dried over Na.sub.2 SO.sub.4 and
concentrated. Flash chromatography (silica, 5-10% MeOH/CH.sub.2
Cl.sub.2) provided 652 mg (50%) of the non-racemic diol. TLC
(silica, 10% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.2. MS
(electrospray): m/z calculated for C.sub.18 H.sub.23.sup.35
ClN.sub.3 O.sub.3 ([M+H].sup.+, 364.14. found 364.1.
B.
(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-py
razolo[4,3-c]pyridin-5-yl]-ethanone.
(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetrah
ydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (452 mg, 1.24 mmol) and
pyridinium p-toluenesulfonate (85 mg) were combined in
MeC(OMe).sub.3 (50 mL) and briefly sonicated. The mixture was
stirred for 17 h, concentrated, and the residue dissolved in
CH.sub.2 Cl.sub.2 (8 mL). The solution was cooled to 0.degree. C.
and treated with AcBr (0.15 mL, 2.0 mmol). After 5 h the mixture
was partitioned between EtOAc (300 mL) and saturated aqueous
NaHCO.sub.3 (75 mL). The EtOAc layer was washed with H.sub.2 O (75
mL) and brine (75 mL), dried over Na.sub.2 SO.sub.4 and
concentrated. The residue was combined with K.sub.2 CO.sub.3 (243
mg, 1.84 mmol) in MeOH (50 mL) and stirred for 3 h then worked up
as described above. Purification by column chromatography (silica,
10-40% acetone/CH.sub.2 Cl.sub.2) gave 159 mg (37%) of the title
compound. Chiral HPLC (Daicel OD, 0.5% Et.sub.2 NH/MeOH) analysis
indicated >95% optical purity. HPLC (reverse phase conditions),
t.sub.R =4.97 min. MS (electrospray): exact mass calculated for
C.sub.18 H.sub.20 ClN.sub.3 O.sub.2 [M.sup.+ +Na], 368.11. m/z
found 368.05. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of amide
rotamers): 7.54 (br d, J=6.3 Hz, 2H), 7.41-7.35 (m, 3H), 7.29 (dd,
J=8.2, 1.9 Hz, 1H), 4.81 and 4.74 (A and B of AB quartet, J.sub.ab
=15.7 Hz, 2H), 4.60 (s, 2H), 4.48 (dd, J=15.2, 2.4 Hz, 1H), 4.42
(dd, J=15.4, 2.8 Hz, 1H), 4.13 (t, J=4.7 Hz, 1H), 4.09 (dd, J=4.6
Hz, 1H), 3.93 (m, 2H), 3.74 (t, J=5.8 Hz, 1H), 3.73 (t, J=5.8 Hz,
1H), 3.34 (m, 2H), 2.85-2.75 (m, 6H), 2.53 (dd, J=4.6, 2.5 Hz, 1H),
2.48 (dd, J=4.6, 2.6 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (s,
3H), 2.15 (s, 3H).
C. 4-(5-Chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid
ethyl ester.
To a solution of 2.03 g (11.6 mmol) of
4-chloro-2-fluoro-nitrobenzene in DMF (12.0 mL) at rt was added
2.00 g (11.6 mmol) of ethyl 4-amino-1-piperidinecarboxylate. A
yellow precipitate formed within 30 min and the reaction was
further diluted with DMF (12.0 mL) and CH.sub.2 Cl.sub.2 (5.0 mL)
and was shaken at 300 RPM overnight. The solvent was removed under
reduced pressure and the resulting solid was dried under vacuum.
The crude product was purified by flash chromatography (silica,
0-5% MeOH/CH.sub.2 Cl.sub.2) to afford 2.83 g (81%) of the title
compound. TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.4. MS
(electrospray): m/z calculated for C.sub.14 H.sub.18 ClN.sub.3
O.sub.4 [M.sup.+ +Na] 350.09, observed 350.0. .sup.1 H NMR (400
MHz, CDCl.sub.3): 8.13 (apparent d, J=9.1 Hz, 2H), 6.84 (d, J=2.0
Hz, 1H), 6.62 (dd, J=9.4, 2.3 Hz, 1H), 4.15 (q, J=14.9, 7.3 Hz,
2H), 4.08 (br d, J=12.4 Hz, 2H), 3.70-3.58 (m, 1H), 3.17-3.05 (m,
2H), 2.07 (br dd, J=13.1, 3.1 Hz, 2H), 1.63-1.50 (m, 2H), 1.28 (t,
J=7.0 Hz, 3H).
D.
4-(6-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic
acid ethyl ester.
To a stirred solution of 0.50 g (1.52 mmol) of
4-(5-chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl
ester in EtOH (15.0 mL) was added concentrated HCl (3.0 mL)
followed by 0.99 g (15.2 mmol) of zinc powder. After 1 h,
additional concentrated HCl (1.5 mL) followed by 0.99 g (15.2 mmol)
of zinc powder was added and the reaction was stirred for 1.5 h.
The mixture was filtered through a pad of celite and was washed
with 5% MeOH/CH.sub.2 Cl.sub.2. The mixture was diluted with
saturated NaHCO.sub.3 and a precipitate formed. The layers were
separated and the aqueous phase was extracted (3.times.5%
MeOH/CH.sub.2 Cl.sub.2). The combined organic layers were dried
over Na.sub.2 SO.sub.4 and the solvent was removed under reduced
pressure to afford a brown oil. The crude oil was diluted with
CH.sub.2 Cl.sub.2 (15.0 mL) and 0.64 mL (4.56 mmol) of Et.sub.3 N
was added followed by 0.45 g (1.52 mmol) of triphosgene. The
reaction was allowed to stir overnight and was then diluted with 1
N NaOH (20 mL) and stirred for an additional 1 h. The layers were
separated and the aqueous phase was extracted with CH.sub.2
Cl.sub.2 (3.times.20 mL). The combined organic extracts were dried
over Na.sub.2 SO.sub.4 and the solvent was removed under reduced
pressure. Purification by flash chromatography (silica, 0-5%
MeOH/CH.sub.2 Cl.sub.2) afforded 0.33 g (67% over 2 steps) of the
title compound. TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f
=0.5. MS (electrospray): m/z calculated for C.sub.15 H.sub.18
ClN.sub.3 O.sub.3 [M.sup.+ +Na] 346.10, observed 346.0. .sup.1 H
NMR (400 MHz, CDCl.sub.3): 9.41 (s, 1H), 7.11 (d, J=2.0 Hz, 1H),
7.04 (d, J=1.8 Hz, 1H), 7.02 (s, 1H), 4.48-4.33 (m, 3H), 4.20 (q,
J=7.1 Hz, 2H), 2.92 (t, J=12.5 Hz, 2H), 2.30 (dq, J=12.9, 4.6 Hz,
2H), 2.10 (d, J=12.6 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).
E. 6-Chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one.
A suspension of 0.20 g (0.62 mmol) of
4-(6-chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic
acid ethyl ester in 10% NaOH (0.62 mL) was heated to 105.degree. C.
for 6 h and then cooled. The solution was adjusted to pH 1 (conc.
HCl) and then back to pH 10 (NaOH). Then, the mixture was diluted
with 5% MeOH/CH.sub.2 Cl.sub.2 (.about.30 mL) until both layers
were clear. The layers were separated and the aqueous phase was
extracted with 5% MeOH/CH.sub.2 Cl.sub.2 (2.times.30 mL). The
combined organic layers were dried over Na.sub.2 SO.sub.4 and the
solvent was removed under reduced pressure to afford 0.12 g (76%)
of a light brown solid. TLC (silica, 10% MeOH/CH.sub.2 Cl.sub.2):
R.sub.f =0.1. MS (electrospray): m/z calculated for C.sub.12
H.sub.14 ClN.sub.3 O [M.sup.+ +H] 252.08, observed 252.1. .sup.1 H
NMR (400 MHz, CDCl.sub.3): 7.27 (d, J=1.6 Hz, 2H), 7.02 (d, J=1.6
Hz, 1H), 7.01 (s, 1H), 4.38 (m, 1H), 3.30 (br d, J=11.9 Hz, 2H),
2.82 (dt, J=12.3, 2.0 Hz, 2H ), 2.35 (dq, J=12.3, 3.5 Hz, 2H), 1.85
(br dd, J=12.1, 2.1 Hz, 2H).
F.
(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyra
zolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dih
ydro-benzoimidazol-2-one.
(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyr
azolo[4,3-c]pyridin-5-yl]-ethanone (31 mg, 0.10 mmol) and
6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (36 mg,
0.17 mmol) were combined in EtOH (0.3 mL) and heated to 70.degree.
C. After 18 h the mixture was allowed to cool, diluted with
CH.sub.2 Cl.sub.2 and purified by preparative TLC (silica, 8%
MeOH/CH.sub.2 Cl.sub.2) to give 7 mg (12%) of the title compound.
HPLC (reverse phase conditions), t.sub.R =3.49 min. MS
(electrospray): m/z calculated for C.sub.30 H.sub.35.sup.35
Cl.sub.2 N.sub.6 O.sub.3 [M.sup.+ +H] 597.22. found 597.20. .sup.1
H NMR (CDCl.sub.3, 400 MHz, a mixture of amide rotamers): 9.16 (br
d, J=10.1 Hz, 1H), 7.55 (br m, 1H), 7.40-7.28 (m, 2H), 7.18 (br s,
1H), 7.03 and 6.98 (A and B of ABX (with fine splittings), J.sub.ab
=8.4 Hz, 2H), 4.85 and 4.74 (A and B of ABX (with fine splittings),
J.sub.ab =15.7 Hz, 1H), 4.62 (s, 1H), 4.29-4.18 (m, 4H), 4.09-4.00
(m, 2H), 3.91-3.71 (m, 2H), 3.16-2.78 (m, 4H), 2.55-2.50 (m, 4H),
2.43 (s, 1.5H), 2.41 (s, 1.5H), 2.23 (m, 1H), 2.21 (s, 1.5H), 2.16
(s, 1.5H), 1.84 (br s, 2H).
Example 7
##STR21##
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-morpholin-4-yl-e
thyl)-1,3-dihydro-benzoimidazol-2-one
A solution of
1-(1-{3-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimi
dazol-2-one (130 mg, 0.22 mmol) in DMF (1 mL) was treated with
cesium carbonate (146 mg, 0.45 mmol) and
4-(2-chloroethyl)morpholine hydrochloride (329 mg, 2.2 mmol) at
25.degree. C. and stirred for 24 h before it was diluted with EtOAc
(10 mL) and H.sub.2 O (5 mL). The organic layer was separated,
washed with H.sub.2 O (2.times.5 mL), dried over Na.sub.2 SO.sub.4,
and concentrated. Column chromatography (silica, 5% MeOH/CH.sub.2
Cl.sub.2) afforded 124 mg (81%) of a white powder. TLC (10%
MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.31. MS (electrospray): m/z
696.3 ([M+H].sup.+, C.sub.36 H.sub.44 F.sub.3 N.sub.7 O.sub.4
requires 695.3). .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of
two rotamers): 7.82 and 7.65 (AB pattern, J.sub.ab =8.2 Hz, 2H),
7.74 and 7.68 (AB pattern, J.sub.ab =8.4 Hz, 2H), 7.23-7.05 (m,
4H), 4.92 and 4.80 (AB pattern, J.sub.ab =15.6 Hz, 1.2H), 4.69 (s,
0.8H), 4.38-4.00 (m, 5H), 4.02 (t, J=7.0 Hz, 2H), 3.92-3.70 (m,
2H), 3.70 (t, J=4.5 Hz, 4H), 3.15-2.80 (m, 4H), 2.70 (t, J=7.1 Hz,
2H), 2.60-2.20 (m, 9H), 2.24 (s, 1.6H), 2.18 (s, 1.4H), 1.85-1.75
(m, 2H).
Example 8
##STR22##
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-b
enzoimidazol-2-one
A.
3-(4-Bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester.
To a stirred solution of 500.0 g (2.51 mol) of
1-tert-butoxycarbonyl-4-piperidone and 87.1 g (2.76 mol) of
morpholine in benzene (1.25 L) was added a catalytic amount
(.about.0.25 g) of p-TsOH. The mixture was heated to reflux for 36
h with a Dean-Stark trap. The solvent was removed under reduced
pressure to give a brown oil, which solidified on standing. The
crude product was divided and 335.0 g (1.25 mol) of the enamine was
diluted with CH.sub.2 Cl.sub.2 (1.25 L) and 175.0 mL (1.25 mol) of
Et.sub.3 N was added. The mixture was cooled to 0.degree. C. and a
solution of 275.0 g (1.25 mol) of 4-bromobenzoyl chloride in
CH.sub.2 Cl.sub.2 (150 mL) was added slowly by dropping funnel over
1 h. The mixture was allowed to warm to rt and stir overnight. The
reaction was then diluted with 1 N HCl (450 mL) and stirred
vigorously for 3 h. The aqueous layer was extracted with CH.sub.2
Cl.sub.2 (3.times.500 mL) and the combined extracts were dried over
Na.sub.2 SO.sub.4 and the solvent was removed under reduced
pressure. The crude oil was diluted with EtOH (850 mL) and cooled
to 0.degree. C. To this stirred solution was slowly added 120.0 g
(3.75 mol) of hydrazine and the mixture was allowed to warm to rt
and stir overnight during which time a white precipitate formed.
The volume of the reaction was reduced to .about.350 mL and EtOAc
(1.50 L) was added to the mixture. The suspension was stirred
vigorously for 2 h and was filtered then washed with EtOAc
(2.times.500 mL) and dried under vacuum to afford 309.0 g (62% over
3 steps) of a white solid. TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2):
R.sub.f =0.3. MS (electrospray): m/z calculated for C.sub.17
H.sub.20 BrN.sub.3 O.sub.2 [M.sup.+ +H] 378.07, observed 378.0.
.sup.1 H NMR (400 MHz, CDCl.sub.3): 7.65-7.26 (m, 4H), 4.64 (br s,
2H), 3.84-3.68 (br m, 2H), 2.87-2.74 (br m, 2H), 1.48 (br s,
9H).
B.
3-(4-Bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium
trifluoroacetate.
To a stirred solution of 10.0 g (26.4 mmol) of the
3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester in CH.sub.2 Cl.sub.2 (26.0 mL) was added 26.0
mL of TFA. The resulting mixture was allowed to stir overnight. The
solvent was removed under reduced pressure and the solid was dried
in vacuo. The dried solid was suspended in Et.sub.2 O and stirred
vigorously for 2 h and then filtered and dried in vacuo to give
10.1 g of a white solid, which was used without further
purification. TLC (silica, 10% MeOH/CH.sub.2 Cl.sub.2): R.sub.f
=0.05. MS (electrospray): m/z calculated for C.sub.12 H.sub.12
BrN.sub.3 [M.sup.+ +H] 278.02, observed 278.0.
C.
3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]
pyridine.
To a stirred solution of 3.11 g (11.1 mmol) of
3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium
trifluoroacetate and 4.71 mL (33.5 mmol) of Et.sub.3 N in DMF (55
mL) was slowly added 1.21 mL (15.6 mmol) of methanesulfonyl
chloride. After 2.5 h, the solvent was removed under reduced
pressure and the residue was diluted with CH.sub.2 Cl.sub.2 (100
mL) and saturated NaHCO.sub.3 (100 mL). The layers were separated
and the aqueous phase was extracted with CH.sub.2 Cl.sub.2
(2.times.30 mL). The combined organic layers were dried over
Na.sub.2 SO.sub.4 and the solvent was removed under reduced
pressure. Purification by column chromatography (silica, 0-5%
MeOH/CH.sub.2 Cl.sub.2) afforded 2.01 g (50%) of the title
compound. TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.3. MS
(electrospray): m/z calculated for C.sub.13 H.sub.14 BrN.sub.3
O.sub.2 S [M.sup.+ +H] 356.00, observed 356.0.
D.
3-(4-Bromo-phenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1
H-pyrazolo[4,3-c]pyridine.
To a stirred solution of 2.50 g (7.00 mmol) of
3-(4-bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]
pyridine and 5.52 mL (70.0 mmol) of epichlorohydrin was added 2.50
g (7.72 mmol) of solid Cs.sub.2 CO.sub.3. The reaction was allowed
to stir for 48 h and the solvent was removed under reduced
pressure. The residue was then diluted with H.sub.2 O (150 mL) and
EtOAc (150 mL). The layers were separated, and the organic layer
was washed with H.sub.2 O (50 mL) and brine (50 mL), dried over
Na.sub.2 SO.sub.4 and the solvent was removed under reduce
pressure. Purification by flash chromatography (silica, 0-20%
acetone/CH.sub.2 Cl.sub.2) afforded 1.52 g (53%) of a white solid.
TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.5. MS
(electrospray): m/z calculated for C.sub.16 H.sub.18 BrN.sub.3
O.sub.3 S [M.sup.+ +H] 412.03, observed 412.0. .sup.1 H NMR (400
MHz, CDCl.sub.3): 7.54 and 7.47 (A and B of AA'BB', J=8.6 Hz, 4H),
4.56-4.45 (m, 3H), 4.10 (dd, J=15.1, 5.4 Hz, 1H), 3.73-3.58 (m,
2H), 3.38-3.32 (m, 1H), 2.96-2.87 (m, 2H), 2.86 (s, 3H), 2.83 (dd,
J=4.4, 4.2 Hz, 1H), 2.48 (dd, J=4.6, 2.6 Hz, 1H).
E.
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-
benzoimidazol-2-one.
A stirred solution of 25.0 mg (0.061 mmol) of
3-(4-bromo-phenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1
H-pyrazolo[4,3-c]pyridine and 19.0 mg (0.073 mmol) of
6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one in EtOH
(0.5 mL) was heated to 80.degree. C. in a sealed vessel for 16 h.
The reaction was cooled and the solvent was removed under reduced
pressure. The crude product was purified by column chromatography
(silica, 0-5% MeOH/CH.sub.2 Cl.sub.2) to afford 0.025 g (63%) of
the title compound. TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2):
R.sub.f =0.4. MS (electrospray): m/z calculated for C.sub.28
H.sub.32 BrClN.sub.6 O.sub.4 S [M.sup.+ +H] 663.11, observed 663.0.
.sup.1 H NMR (400 MHz, CDCl.sub.3): 10.2 (s, 1H), 7.52 and 7.46 (A
and B of AA'BB', J=8.6 Hz, 4H), 7.15 (br d, J=1.5 Hz, 1H),
7.04-6.95 (m, 2H), 4.52 and 4.49 (A and B of AB quartet, J.sub.ab
=14.5 Hz, 2H), 4.33-4.14 (m, 3H), 4.07-3.97 (m, 1H), 3.74-3.58 (m,
2H), 3.17-2.89 (m, 4H), 2.86 (s, 3H), 2.57-2.30 (m, 5H), 2.20 (t,
J=11.1 Hz, 1H), 1.87-1.73 (m, 2H).
Example 9
##STR23##
[3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro
-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-ben
zoimidazol-1-yl]-acetonitrile
A.
3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-
carboxylic acid tert-butyl ester.
To a stirred solution of 500 g (2.51 mol) of
1-tert-butoxycarbonyl-4-piperidone and 87.1 g (2.76 mol) of
morpholine in benzene (1.25 L) was added a catalytic amount
(.about.0.25 g) of p-TsOH. The mixture was heated to reflux for 36
h with a Dean-Stark trap. One half of the solvent was removed under
reduced pressure and the resulting solution was cooled and
filtered. The filtrate was then concentrated to yield 630 g (94%)
of an orange red oil. The eneamine was divided and 320 g (1.19 mol)
was diluted with CH.sub.2 Cl.sub.2 (1.0 L) and 165.0 mL (1.19 mol)
of Et.sub.3 N was added. The mixture was cooled to 0.degree. C. and
a solution of 225 g (1.08 mol) of 4-trifluoromethylbenzoyl chloride
in CH.sub.2 Cl.sub.2 (0.5 L) was added slowly by dropping funnel
over 1 h. The mixture was allowed to warm to rt and stir overnight.
The reaction was then diluted with 1 N HCl (450 mL) and stirred
vigorously for 3 h. The aqueous layer was extracted with CH.sub.2
Cl.sub.2 (3.times.500 mL) and the combined extracts were dried over
Na.sub.2 SO.sub.4 and the solvent was removed under reduced
pressure. The crude oil was diluted with EtOH (1 L) and cooled to
0.degree. C. To this stirred solution was slowly added 115 g (3.57
mol) of hydrazine and the mixture was allowed to warm to rt and
stir overnight during which time a white precipitate formed. The
volume of the reaction was reduced to .about.500 mL and cooled. The
precipitate was collected to afford 285 g (72% from eneamine) of a
white solid. .sup.1 H NMR (400 MHz, CDCl.sub.3): 7.63-7.55 (m, 4H),
4.58 (br s, 2H), 3.69-3.62 (br m, 2H), 2.74-2.68 (br m, 2H), 1.47
(s, 9H).
B.
1-(2-Methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydr
o-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester.
3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-c
arboxylic acid tert-butyl ester (1.85 g, 5.04 mmol) and methyl
acrylate (0.50 mL, 5.6 mmol) were combined in toluene (30 mL) and
heated to 75.degree. C. The resulting mixture was treated with
t-BuONa (100 mg), and heating continued for 48 h. The mixture was
allowed to cool and partitioned between EtOAc (300 mL) and
NaHCO.sub.3 (75 mL). The aqueous layer was extracted with EtOAc
(3.times.75 mL). The combined extracts were dried over Na.sub.2
SO.sub.4 and concentrated. Column chromatography (silica, 30-60%
EtOAc/hexanes) afforded 343 mg (15%) of the title compound. TLC
(silica, 50% EtOAc/hexanes): R.sub.f =0.4. MS (electrospray): m/z
calculated for C.sub.22 H.sub.27 F.sub.3 N.sub.3 O.sub.4 [M.sup.+
+H] 454.20. found 454.1. .sup.1 H NMR (CDCl.sub.3, 400 MHz): 7.75
(br d, J=8.1 Hz, 2H), 7.64 (br s, 2H), 4.63 (br s, 2H), 4.30 (t,
J=6.6 Hz, 2H), 3.75 (br s, 2H), 3.68 (s, 3H), 2.98 (t, J=6.6 Hz,
2H), 2.79 (br t, J=5.6 Hz, 2H), 1.48 (s, 9H).
C.
1-(3-Hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyraz
olo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester.
A solution of LiBH.sub.4 (26 mg, 1.2 mmol) in THF (0.5 mL) was
added to a 0.degree. C. solution of
1-(2-methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydr
o-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (317
mg, 0.70 mmol) in THF (4.0 mL). The mixture was stirred for 5 min
then additional LiBH.sub.4 (15 mg) was added and stirring continued
for 17 h. The mixture was partitioned between EtOAc (80 mL) and
saturated aqueous NaHCO.sub.3 (20 mL). The aqueous layer was
extracted with EtOAc (2.times.20 mL). The combined extracts were
dried over Na.sub.2 SO.sub.4 and concentrated. Column
chromatography (silica, 0-8% MeOH/CH.sub.2 Cl.sub.2) afforded 268
mg (95%) of the title compound. HPLC (reverse phase conditions),
t.sub.R =6.82 min. MS (electrospray): m/z calculated for C.sub.21
H.sub.26 F.sub.3 N.sub.3 O.sub.3 [M.sup.+ +Na] 448.18. found
448.10. .sup.1 H NMR (CDCl.sub.3, 400 MHz): 7.73 (br d, J=8.2 Hz,
2H), 7.65 (br s, 2H), 4.64 (br s, 2H), 4.21 (t, J=6.4 Hz, 2H), 3.76
(br s, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.73 (br t, J=5.4 Hz 2H), 2.04
(q, J=6.1, 2H), 1.48 (s, 9H).
D. 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester.
1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (7.24 g, 34.1
mmol) and di-tert-butyl dicarbonate (9.12 g, 41.0 mmol) were
combined in DMF (80 mL) and the mixture heated to 40.degree. C.
under N.sub.2 for 17 h. The mixture was allowed to cool, diluted
with EtOAc (800 mL) and washed with saturated aq. NaHCO.sub.3 (150
mL), H.sub.2 O (3.times.150 mL) and brine (150 mL). The combined
aqueous washes were extracted with EtOAc (2.times.150 mL). The
combined extracts were dried over Na.sub.2 SO.sub.4 and
concentrated to afford 12.4 g of the title compound. TLC (silica,
50% EtOAc/hexanes): R.sub.f =0.3. MS (electrospray): m/z calculated
for C.sub.17 H.sub.23 N.sub.3 O.sub.3 [M.sup.+ +Na] 340.16. found
340.1. .sup.1 H NMR (CDCl.sub.3, 400 MHz): 10.59 (s, 1H), 7.15-7.11
(m, 2H), 7.08-7.02 (m, 2H), 4.49 (tt, J=8.4, 4.0 Hz, 1H), 4.32 (br
s, 2H), 2.89 (br t, J=11.6, 2H), 2.34 (dq, J=12.6, 4.4 Hz, 2H),
1.83 (br d, J=10.5 Hz, 2H) 1.36 (s, 9H).
E.
(2-Oxo-3-piperidin-4-yl-2,3-dihydro-benzoimidazol-1-yl)-acetonitrile.
A solution of
4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester (2.91 g, 9.16 mmol) in THF (10 mL) was added
dropwise to a solution of KHMDS (2.19 g, 11.0 mmol) in THF (20 mL).
The mixture was stirred for 10 min then bromoacetonitrile (3.2 mL,
46 mmol) was added. The resulting mixture was stirred for 4 h then
partitioned between EtOAc (750 mL) and saturated aqueous
NaHCO.sub.3 (200 mL). The EtOAc layer was washed with H.sub.2 O
(3.times.200 mL) and brine (200 mL). The combined washes were
extracted with EtOAc (2.times.150 mL). The combined extracts were
dried over Na.sub.2 SO.sub.4 and concentrated. Column
chromatography (silica, 20-60% EtOAc/hexanes) afforded 2.20 g (67%)
of
4-(3-cyanomethyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbox
ylic acid tert-butyl ester. The purified material was dissolved in
CH.sub.2 Cl.sub.2 (40 mL) and diluted with TFA (25 mL). The
resulting mixture was stirred for 1 h then diluted with CH.sub.2
Cl.sub.2 (250 mL) and washed with 1 N NaOH (100 mL). The aqueous
layer was extracted with CH.sub.2 Cl.sub.2 (2.times.100 mL). The
combined extracts were dried over Na.sub.2 SO.sub.4 and
concentrated to 1.59 g (95%) of the title compound which was
suitable for further use without purification. TLC (silica, 5%
MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.1. MS (electrospray): m/z
calculated for C.sub.14 H.sub.17 N.sub.4 O [M.sup.+ +H] 257.14.
found 257.1. .sup.1 H NMR (CDCl.sub.3, 400 Hz): 733-7.29 (m, 1H),
7.17-7.02 (m, 3H), 4.75 (s, 2H), 4.41 (tt, J=12.2, 4.4 Hz, 1H),
3.28 (br d, J=9.8 Hz, 2H), 3.11 (br s, 1H), 2.80 (t, J=10.0 Hz,
2H), 2.37 (dq, J=12.5, 4.2 Hz, 2H), 1.83 (br d, J=11.8 Hz, 2H).
F.
[3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydr
o-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-acetonitrile.
1-(3-Hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (268 mg, 0.63
mmol) was dissolved in CH.sub.2 Cl.sub.2 (10 mL) and TFA (10 mL).
The mixture was stirred for 1 h then concentrated to dryness. The
residue was dissolved in CH.sub.2 Cl.sub.2 (4.0 mL), cooled to
0.degree. C. and treated with i-Pr.sub.2 NEt (0.36 mL, 2.1 mmol),
followed by methanesulfonyl chloride (0.16 mL, 2.1 mmol). The
reaction mixture was stirred for 4 h, then diluted with EtOAc (200
mL) and washed with saturated aqueous NaHCO.sub.3 (2.times.25 mL).
The washes were extracted with EtOAc (2.times.25 mL). The combined
extracts were dried over Na.sub.2 SO.sub.4 and concentrated. A
portion of the crude mesylate (197 mg, ca. 0.41 mmol) was combined
with
(2-oxo-3-piperidin-4-yl-2,3-dihydro-benzoimidazol-1-yl)-acetonitrile
(321 mg, 1.25 mmol) in CH.sub.2 Cl.sub.2 (2.0 mL) and DMF (0.5 mL).
The resulting mixture was treated with i-Pr.sub.2 NEt (0.22 mL, 1.3
mmol) and stirred for 60 h. The reaction mixture was partitioned
between EtOAc (150 mL) and saturated aqueous NaHCO.sub.3 (75 mL).
The EtOAc layer was washed with H.sub.2 O (2.times.75 mL), and
brine (75 mL). The combined washes were extracted with EtOAc
(3.times.50 mL). The combined extracts were dried over Na.sub.2
SO.sub.4 and concentrated. Purification of the residue by
preparative TLC (silica, 1% MeOH/CH.sub.2 Cl.sub.2 then 25%
acetone/CH.sub.2 Cl.sub.2) gave 37 mg (14%) of the title compound.
HPLC (reverse phase conditions), t.sub.R =2.94 min. MS
(electrospray): m/z calculated for C.sub.31 H.sub.35 F.sub.3
N.sub.7 O.sub.3 S [M.sup.+ +H] 642.25, found 642.25. .sup.1 H NMR
(CDCl.sub.3, 400 MHz): 7.73 and 7.76 (A and B of AA'BB' J.sub.ab
=8.2 Hz, 4H), 7.26-7.05 (m, 4H), 4.81 (s, 2H), 4.56 (s, 2H), 4.26
(m, 1H), 4.15 (t, J=6.8 Hz, 2H), 3.70 (t, J=5.8 Hz, 2H), 3.03 (br
d, J=11.1 Hz, 2H), 2.95 (t, J=5.7 Hz, 2H), 2.91 (s, 3H), 2.43 (m,
4H), 2.12 (m, 4H), 1.82 (br d, J=9.9 Hz, 2H).
Example 10
##STR24##
5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-
dihydro-benzoimidazol-2-one
A. 1-Methanesulfonyl-piperidin-4-one.
Potassium carbonate (324 g, 2340 mmol) was added to a solution of
4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in
chloroform (300 mL) and water (300 mL). The slurry was cooled to
0.degree. C. and treated with methylsulfonyl chloride (136 mL, 1760
mmol) by dropwise addition over a 1 h period. The reaction mixture
was allowed to shake for 72 h and was partitioned between CH.sub.2
Cl.sub.2 (500 mL) and saturated aqueous NaHCO.sub.3 (500 mL). The
aqueous layer was extracted with CH.sub.2 Cl.sub.2 (3.times.200
mL). The organic layer was washed with 1% KHSO.sub.4 (250 mL),
dried (Na.sub.2 SO.sub.4), and concentrated to afford 90.5 g (87%)
of a white solid. HPLC (reverse phase conditions), t.sub.R =2.19
min. MS (electrospray): exact mass calculated for C.sub.6 H.sub.11
NO.sub.3 S, 177.1. m/z found, 178.1 [M+H].sup.+. .sup.1 H NMR (400
MHz, CDCl.sub.3): 3.60 (t, J=6.5 Hz, 4H), 2.89 (s, 3H), 2.59 (t,
J=6.3 Hz, 4H).
B.
5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyraz
olo[4.3-c]pyridine.
p-Toluenesulfonic acid (1.34 g, 7.0 mmol) and morpholine (25.83 mL,
296 mmol) were added to a solution of
1-methanesulfonyl-piperidin-4-one (50.0 g. 282 mmol) in benzene
(282 mL). The reaction mixture was heated in a flask equipped with
a condenser and a Dean-Stark trap at reflux for 15 h. The reaction
mixture was cooled and concentrated in vacuo to give the enamine
which was used without further purification. The enamine was
dissolved in CH.sub.2 Cl.sub.2 (200 mL) and cooled to 0.degree. C.
To this was added triethylamine (47.2 mL, 339 mmol) followed by
dropwise addition of 4-trifluoromethylbenzoyl chloride (42.3 mL,
285 mmol) dissolved in CH.sub.2 Cl.sub.2 (82 mL). The reaction
mixture was allowed to warm to room temperature and stirred for 20
h. The reaction mixture was washed with 1 N HCl (250 mL) and the
CH.sub.2 Cl.sub.2 layer was separated, dried (Na.sub.2 SO.sub.4),
and concentrated. The resulting oil was taken up in ethanol (300
mL) and treated with hydrazine (44.3 mL, 1.41 mol) at 0.degree. C.
The reaction mixture was allowed to warm to room temperature and
stirred for 24 h. The mixture was concentrated and the resulting
solid was filtered with ethanol wash and dried in vacuo to afford
70 g (72%) of
5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyraz
olo[4,3-c]pyridine as a white solid. HPLC (reverse phase
conditions), t.sub.R =6.33 min. MS (electrospray): exact mass
calculated for C.sub.14 H.sub.14 F.sub.3 N.sub.3 O.sub.2 S, 345.0.
m/z found, 346.0 [M+H].sup.+. .sup.1 H NMR (400 MHz, CDCl.sub.3):
7.72 (s, 4H), 4.58 (s, 2H), 3.69 (t, J=5.7 Hz, 2H), 2.99 (t, J=5.7
Hz, 2H), 2.92 (s, 3H).
C.
3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-propan-1-ol.
Cs.sub.2 CO.sub.3 (33.74 g, 103.5 mmol) was added to a solution of
5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyraz
olo[4,3-c]pyridine (29.8 g, 86.3 mmol) in anhydrous DMF (70 mL) and
stirred for 25 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol)
was added and stirred under N.sub.2 at room temperature for 18 h.
Water (500 mL) was added to the reaction and stirred for 5 min. The
precipitated material was filtered out and washed with water
(4.times.100 mL) and dried in a Freeze Drying System. The crude
material (31.0 g) was taken up in anhydrous DMF (65 mL) and
Cs.sub.2 CO.sub.3 (33.74 g, 103.5 mmol) was added, and stirred for
10 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) and MeOH
(6.0 mL, 4.75 g, 148 mmol) were added and stirring continued under
N.sub.2 at rt for 15 h. Water (500 mL) was added to the reaction
and stirred for 10 min. The precipitated material was filtered and
washed with water (3.times.100 mL). The filter cake was dissolved
in CH.sub.2 Cl.sub.2 (200 mL) and washed with brine (50 mL), dried
(Na.sub.2 SO.sub.4), and concentrated. The solid was triturated
with Et.sub.2 O (200 mL), filtered, then washed with Et.sub.2 O,
and dried to furnish 16.0 g of the desired compound. The mother
liquor was chromatographed (silica, 0-10% acetone/EtOAc) to obtain
an additional 3.0 g of the title compound. The combined yield was
54.6%. MS (electrospray): exact mass calculated for C.sub.17
H.sub.20 F.sub.3 N.sub.3 O.sub.3 S, 403.12. m/z found, 404.0
[M+H].sup.+, 426.0 [M+Na].sup.+. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 7.71 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 4.55
(s, 2H), 4.23 (t, J=6.5 Hz, 2H), 3.70-3.63 (m, 4H), 2.90 (s, 3H),
2.90 (t, J=5.1 Hz, 2H), 2.62 (t, J=5.9 Hz, 1H), 2.06 (q, J=6.1 Hz,
2H).
D.
5-Chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one.
To a stirred suspension of 0.97 g (2.99 mmol) of
4-(6-chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic
acid ethyl ester in THF (30 mL) was added 0.5 M KHMDS in toluene.
This mixture was stirred for 1 h and 0.25 mL (3.89 mmol) of Mel was
added in one portion. After 1.5 h the reaction was diluted with 1 N
HCl (75 mL) and EtOAc (75 mL). The layers were separated, and the
organic layer was washed with H.sub.2 O (50 mL) and brine (50 mL),
dried over Na.sub.2 SO.sub.4 and the solvent was removed under
reduced pressure. Purification by flash chromatography (silica,
0-5% MeOH/CH.sub.2 Cl.sub.2) afforded 0.92 g (91%) of a white
solid. A suspension of 0.92 g (2.72 mmol) of the ethyl carbamate in
1:1 EtOH (7.0 mL) and 10% NaOH (7.0 mL) was heated to 110.degree.
C. for 36 h and then cooled. The mixture was diluted with EtOAc (30
mL) and H.sub.2 O. The layers were separated and the aqueous phase
was extracted with EtOAc (2.times.30 mL). The combined organic
layers were dried over Na.sub.2 SO.sub.4 and the solvent was
removed under reduced pressure to afford 0.56 g (78%) of a pale
yellow solid. TLC (silica, 10% MeOH/CH.sub.2 Cl.sub.2): R.sub.f
=0.1. MS (electrospray): m/z calculated for C.sub.13 H.sub.16
ClN.sub.3 O [M.sup.+ +H] 266.10, observed 266.0. .sup.1 H NMR (400
MHz, CDCl.sub.3): 7.28 (d, J=1.8 Hz, 2H), 7.05 (dd, J=8.3, 2.0 Hz,
1H), 6.87 (d, J=8.3 Hz, 1H), 4.41 (tt, J=12.5, 4.3 Hz, 1H), 3.39
(s, 3H), 3.30 (br d, J=11.9 Hz, 2H), 2.82 (dt, J=12.4, 2.0 Hz, 2H
), 2.30 (dq, J=12.3, 4.3 Hz, 2H), 1.81 (br dd, J=12.1, 2.3 Hz,
2H).
E.
5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3
-dihydro-benzoimidazol-2-one.
To a stirred solution of 0.33 mL (3.72 mmol) of oxalyl chloride in
CH.sub.2 Cl.sub.2 (10 mL) under N.sub.2 at -78.degree. C. was added
0.36 mL (4.96 mmol) of DMSO and the reaction was stirred for 15
min. To this solution was added a solution of 1.0 g (2.48 mmol) of
3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-propan-1-ol in 10 mL over 10 min and
stirring was continued for 25 min. To this solution was added 1.40
mL (9.92 mmol) of Et.sub.3 N and the reaction was stirred for 10
min at -78.degree. C. and was then allowed to warm to rt and stir
for 1 h. The mixture was diluted with EtOAc (75 mL) and saturated
NaHCO.sub.3 (75 mL) and the layers were separated. The combined
organic layers were dried over Na.sub.2 SO.sub.4 and the solvent
was removed under reduced pressure. The resulting solid was dried
in vacuo and was suspended in Et.sub.2 O (20 mL) and stirred
vigorously for 1 h. The solid was filtered and washed with Et.sub.2
O (2.times.10 mL) to afford the crude aldehyde which was carried on
without further purification. The crude aldehyde,
5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one
(0.60 g, 2.3 mmol), and 0.20 mL (3.72 mmol) of AcOH was dissolved
in CH.sub.2 Cl.sub.2 (15 mL) followed by 0.69 g (3.25 mmol) of
NaBH(OAc).sub.3, and the reaction was allowed to stir overnight.
The mixture was diluted with CH.sub.2 Cl.sub.2 (75 mL) and
saturated NaHCO.sub.3 (75 mL) and the layers were separated. The
combined organic layers were dried over Na.sub.2 SO.sub.4 and the
solvent was removed under reduced pressure. Purification by flash
chromatography (silica, 0-4% MeOH/CH.sub.2 Cl.sub.2) afforded 1.28
g (79% over 2 steps) of a white solid. TLC (silica, 5%
MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.5. MS (electrospray): m/z
calculated for C.sub.30 H.sub.34 ClF.sub.3 N.sub.6 O.sub.3 S
[M.sup.+ +H] 651.21, observed 651.2. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 7.71 and 7.63 (A and B of AA'BB", J.sub.AB =8.17 Hz,
4H), 7.16 (d, J=1.8 Hz, 1H), 7.04 (d, J=8.3, 1.8 Hz, 1H), 6.86 (d,
J=8.3 Hz, 1H), 4.55 (s, 2H), 4.23 (tt, J=12.4, 4.3 Hz, 1H), 4.13
(t, J=6.7 Hz, 2H), 3.69 (t, J=5.7 Hz, 2H), 3.36 (s, 3H), 3.0 (d,
J=11.6 Hz 2H), 2.95 (t, J=5.7 Hz, 2H), 2.90 (s, 3H), 2.45-2.32 (m,
4H), 2.16-2.04 (m, 4H), 1.76 (dd, J=11.9, 2.0 Hz, 2H). .sup.13 C
NMR (100 MHZ, CDCl.sub.3): 171.0, 153.7, 144.7, 137.1, 136.8,
129.3, 129.0, 128.7, 126.4, 125.5 (q, J=3.8 Hz), 122.7, 120.7,
109.8, 109.2, 108.0, 60.3, 54.7, 53.0, 51.3, 46.8, 43.1, 42.4,
36.8, 29.0, 27.2, 27.0, 22.3, 21.0, 14.1.
Example 11
##STR25##
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-on
e
A. Methyl 2-nitrophenylacetate.
2-Nitrophenylacetic acid (60 g, 0.3 mol) was set stirring in 250 mL
of methanol. Sulfuric acid (0.5 mL) was added and the mixture
heated to reflux. After 20 h the mixture was cooled and evaporated
under reduced pressure to give a clear yellow oil. The oil was
brought up in EtOAc and washed with saturated NaHCO.sub.3. The
organics were dried (MgSO.sub.4) and evaporated to give 63 g (98%)
of the ester as a clear orange liquid. TLC (silica, 25%
EtOAc/hexanes): R.sub.f =0.36. .sup.1 H NMR (400 MHz, CDCl.sub.3):
8.24 (m, 1H), 7.16 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 4.15 (s,
2H), 3.83 (s, 3H).
B. Methyl 2-aminophenylacetate.
Methyl 2-nitrophenylacetate (10.1 g, 51.2 mmol) in 125 mL of
methanol containing 221 mg of 10% Pd/C was placed on the Parr
hydrogenator at 40 psi. After 5 h the mixture was filtered through
celite and evaporated under reduced pressure to give a clear red
oil. The solvent was evaporated under reduced pressure to give 8.5
g (100%) of methyl 2-aminophenylacetate as a clear red oil. TLC
(silica, EtOAc/hexanes): R.sub.f =0.24. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 7.21 (m, 2H), 6.86 (m, 2H), 3.81 (s, 3H), 3.70 (s,
2H).
C. 4-(2-Oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid
tert-butyl ester.
Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and
1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set
stirring in 50 mL of CH.sub.2 Cl.sub.2 under an atmosphere of
nitrogen. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added
followed by 1 mL of acetic acid. After 20 h at rt the mixture was
quenched by the slow addition of saturated NaHCO.sub.3. After
stirring for 30 min, the organics were separated, dried
(MgSO.sub.4), and evaporated to afford 7.5 g of a purple oil.
Purification by column chromatography (silica, 10-50%
EtOAc/hexanes) gave 3.9 g (62%) of the title compound. TLC (silica,
25% EtOAc/hexanes): R.sub.f =0.15. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 7.25 (m, 2H), 7.01 (m, 2H), 4.40 (m, 1H), 3.53 (s,
2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.51 (s, 9H).
D. 1-Piperidin-4-yl-1,3-dihydro-indol-2-one.
4-(2-Oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid
tert-butyl ester (3.9 g, 12.3 mmol) was set stirring in 30 mL of
1:1 TFA/CH.sub.2 Cl.sub.2. After 45 min the solvent was evaporated
under reduced pressure to give a clear purple oil. The oil was
brought up in diethyl ether and cooled on ice to give a
precipitate. The solid was filtered, washed with ether and air
dried to give 4.0 g (100%) of the title compound as a TFA salt.
.sup.1 H NMR (400 MHz, DMSO-d.sub.6): 8.6 (br s, 1H), 7.27 (m, 3H),
7.03 (m, 1H), 4.45 (m, 1H), 3.56 (s, 2H), 3.42 (m, 2H), 3.09 (m,
2H), 2.53 (m, 2H), 1.78 (m, 2H).
E.
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro
-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-o
ne.
3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-1-yl]-propan-1-ol (304 mg, 0.754 mmol) was set
stirring in 5 mL of CH.sub.2 Cl.sub.2 at rt under nitrogen.
Dess-Martin reagent (394 mg, 0.929 mmol) was added in one portion
and the reaction mixture was left stirring. After 1.5 h the mixture
was added to a stirring solution of thiosulphate (10 equiv) in 20
mL of water and 5 mL of saturated NaHCO.sub.3. After 2 h the
organic layer was separated, dried (MgSO.sub.4) and evaporated to
give the aldehyde as a light yellow solid. The above aldehyde (303
mg, 0.754 mmol) and 1-piperidin-4-yl-1,3-dihydro-indol-2-one were
set stirring in 15 mL of CH.sub.2 Cl.sub.2 containing Et.sub.3 N
(0.15 mL, 1.1 mmol). A solution of Na(AcO).sub.3 BH in 5 mL of
CH.sub.2 Cl.sub.2 was added dropwise via pipette over 10 min and
the mixture was left to stir overnight. The mixture was quenched
with saturated NaHCO.sub.3 and the organic layer separated. The
organics were dried (MgSO.sub.4) and evaporated to a clear purple
oil. Purification with column chromatography (silica, 50-100%
acetone/CH.sub.2 Cl.sub.2) gave 240 mg (53%) of a light pink solid.
TLC (silica, 50% acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.17. .sup.1
H NMR (400 MHz, DMSO-d.sub.6): 7.82 (m, 4H), 7.24 (m, 2H), 7.11 (m,
1H), 6.98 (m, 1H), 4.49 (s, 2H), 4.12 (m, 3H), 3.54 (s, 2H) 3.32
(s, 4H), 2.95 (m, 7H), 2.32 (m, 4H), 1.99 (m, 4H), 1.55 (m,
2H).
Example 12
##STR26##
1-[3-(4-Chloro-3-methyl-phenyl)-1-(3-{4-[3-(4-chloro-phenyl)-[1,2,4]oxadiaz
ol-5-yl]-piperidin-1-yl}-2-hydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-
c]pyridin-5-yl]-ethanone
1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazol
o[4,3-c]pyridin-5-yl]-ethanone (0.069 g. 0.20 mmol) was dissolved
in CH.sub.2 Cl.sub.2 (1 mL), and
4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine (0.105 g, 0.4
mmol) was added, followed by Yb(OTf).sub.3 (0.031 g, 0.22 mmol).
The mixture was stirred at room temperature for 16 h. Preparative
TLC (silica, 7.5% MeOH/CH.sub.2 Cl.sub.2) afforded 84 mg (69%) of
the title compound. MS (electrospray): exact mass calculated for
C.sub.31 H.sub.34 Cl.sub.2 N.sub.6 O.sub.3, 608.21. m/z found,
609.2 [M.sup.+ +H]. .sup.1 H NMR (400 MHz, CDCl.sub.3, 1:1 mixture
of rotamers): 8.00 (d, J=8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.48-7.42
(d, J=8.6 Hz, 2H), 7.41-7.30 (m, 2H), 4.84 and 4.73 (A and B of AB
quartet J=15.6 Hz, 1H), 4.62 (br s, 1H), 4.25-4.13 (m, 2H),
4.10-3.98 (m, 2H), 3.90-3.70 (m, 2H), 3.04-2.71 (m, 5H), 2.51-2.40
(m, 6H), 2.30-2.15 (m, 6H), 2.10-1.90 (m, 2H).
Example 13
##STR27##
1-[1-{2-Hydroxy-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]-
propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-5-yl]-ethanone
A. 2-Piperidin-4-yl-5-trifluoromethyl-benzothiazole.
To a stirred solution of 5 g (29.2 mmol) of
1-acetyl-piperidine-4-carboylic acid in toluene (100 mL) and a
catalytic amount of DMF (1 mL) was added dropwise 2.4 mL of oxalyl
chloride (33.3 mmol). The reaction mixture was allowed to stir at
room temperature overnight. A 20 mL aliquot (6 mmol) of the acid
chloride solution was then placed in a separate flask and treated
with a solution of 1.4 g (6.10 mmol) of
2-amino-4-(trifluoromethyl)thiophene hydrochloride in triethyl
amine (4 mL). The reaction was then heated to 80.degree. C. for 30
min and then partitioned between ethyl acetate (50 mL) and water
(20 mL) and separated. The aqueous layer was further extracted with
EtOAc (2.times.30 mL). The combined organic layers were then washed
with water (25 mL), brine, dried over Na.sub.2 SO.sub.4, and the
solvent was removed under reduced pressure. This was then heated to
60.degree. C. in a 1 N HCl/MeOH solution overnight with stirring.
The reaction mixture was cooled and concentrated to dryness. The
solid was then taken back up in 35 mL MeOH and stirred over sodium
bicarbonate (1 g) for 1 h then filtered and stripped to give 1.05 g
(60%) of the desired product which was used without further
purification. MS (electrospray): exact mass calculated for C.sub.13
H.sub.13 F.sub.3 N.sub.2 S, 286.08. m/z found, 287.1 [M+H].sup.+.
.sup.1 H NMR (CDCl.sub.3, 400 MHz): 8.25 (s, 1H), 7.98 (d, J=8.41
Hz, 1H), 7.65 (d, J=8.41 Hz, 1H), 3.38 (tt, J=11.35, 4.11 Hz, 1H),
3.28 (ddd, J=13.69, 11.74, 2.74 Hz, 1H), 3.16 (ddd, J=13.89, 11.15,
2.74 Hz, 1H), 2.85 (m, 1H), 2.25 (br m, 2H), 1.97 (br m, 2H).
B.
1-[1-{2-Hydroxy-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]
-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-5-yl]-ethanone.
A solution of 63 mg (0.22 mmol)
2-piperidin-4-yl-5-trifluoromethyl-benzothiazole was dissolved in 4
mL EtOH and treated with 40 mg (0.11 mmol) of
1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to
60.degree. C. overnight. The solvent was then removed by rotary
evaporation and the crude product was purified by column
chromatography (silica, 0-10% MeOH/EtOAc) to afford 57 mg (80%) of
a white solid. MS (electrospray): exact mass calculated for
C.sub.31 H.sub.31 F.sub.6 N.sub.5 O.sub.2 S, 651.21. m/z found,
652.2 [M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of
amide rotamers): 8.24 (s, 1H), 7.97 (d, J=8.41 Hz, 1H), 7.78 (d,
J=8.41 Hz, 1H), 7.70 (m, 2H), 7.65 (d, J=8.41 Hz, 1H), 7.60 (dd,
J=8.41, 1.37 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.85
Hz, 1H), 4.66 (br s, 1H), 4.25-4.15 (m, 2H), 4.08-3.99 (m, 1.5H),
3.91-3.83 (m, 0.5H), 3.82-3.68 (m, 1H), 3.16 (tt, J=11.35, 3.52 Hz,
1H), 3.12-3.06 (m, 1H), 3.02-2.97 (m, 1H), 2.9-2.87 (m, 1.4H),
2.87-2.75 (m, 0.6H), 2.55-2.43 (m, 3H), 2.27-2.17 (m, 3H), 2.21 (s,
1.5H), 2.17 (s, 1.5H), 2.04-1.87 (m, 2H).
Example 14
##STR28##
1-[1-{3-[4-(Benzo[d]isoxazol-3-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(
4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-e
thanone
A. 4-(Benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester.
To a stirred solution of 263 mg of
t-butyl-4-hydroxy-1-piperidinecarboxylate (1.3 mmol) in 5 mL of dry
DMF was added 52 mg of 60% NaH in mineral oil (1.3 mmol). After
stirring at room temperature for 10 min, 100 mg (0.65 mmol) of
3-chloro-1,2-benzisoxazole in DMF (1 mL) was added. The mixture was
stirred at 40.degree. C. overnight and then partitioned between
EtOAc (50 mL) and water (20 mL) and separated. The aqueous layer
was further extracted with EtOAc (2.times.30 mL). The combined
organic layers were then washed with water (25 mL), brine, dried
over Na.sub.2 SO.sub.4, and the solvent was removed under reduced
pressure to give crude product. Purification by chromatography
(silica, gradient elution of 40% hexanes/CH.sub.2 Cl.sub.2 to
100%CH.sub.2 Cl.sub.2) gave 176 mg (85%) product as a light yellow
solid. MS (electrospray): exact mass calculated for C.sub.17
H.sub.22 N.sub.2 O.sub.4, 318.16. m/z found, 341.1 [M+Na].sup.+.
.sup.1 H NMR (CDCl.sub.3, 400 MHz): 7.64 (dt, J=8.02, 1.17 Hz, 1H),
7.53 (ddd, J=8.41, 7.04, 1.17 Hz, 1H), 7.43 (dt, J=8.41, 0.78 Hz,
1H), 7.27 (ddd, J=8.02, 7.04, 0.78 Hz, 1H), 5.07 (m, 1H), 3.87-3.77
(br m, 2H), 3.30 (m, 2H), 2.17-2.10 (br m, 2H), 1.93-1.84 (br m,
2H), 1.48 (s, 9H).
B.
1-[1-{3-[4-(Benzo[d]isoxazol-3-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-
(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-
ethanone.
A solution of 176 mg (0.55 mmol) of
4-(benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester in CH.sub.2 Cl.sub.2 (2 mL) was treated with
trifluoroacetic acid (0.5 mL) at room temperature overnight. The
solvent was then removed and the crude product dissolved in
methanol and stirred over 100 mg of sodium bicarbonate for 1 h, the
solid was then filtered off and the filtrate concentrated. The
crude piperidine was then dissolved in 4 mL EtOH and treated with
202 mg (0.55 mmol) of
1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone The solution was heated to
60.degree. C. overnight. The solvent was then removed by rotary
evaporation and the crude product was purified by column
chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (68%) of
a white solid. MS (electrospray): exact mass calculated for
C.sub.30 H.sub.32 F.sub.3 N.sub.5 O.sub.4, 583.24. m/z found, 584.2
[M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of amide
rotamers): 7.77 (d, J=8.22 Hz, 1H), 7.69 (m, 2H), 7.66-7.61 (m,
2H), 7.54-7.49 (m, 1H), 7.41 (d, J=8.41 Hz, 1H), 7.28-7.23 (m, 1H),
4.93 (br m, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz,
1H), 4.65 (br s, 1H), 4.24-4.18 (m, 0.75H), 4.18-4.09 (m, 1.25H),
4.07-3.98 (m, 1.5H), 3.91-3.79 (m, 0.5H), 3.79-3.67 (m, 1H),
3.02-2.85 (m, 2.4H), 2.85-2.70 (m, 1.6H), 2.61-2.52 (m, 1H),
2.51-2.40 (m, 2H), 2.39-2.30 (m, 1H), 2.24-2.12 (br m, 2H), 2.20
(s, 1.5H), 2.16 (s, 1.5H), 2.02-1.86 (m, 2H).
Example 15
##STR29##
1-[1-{3-[4-(5-Chloro-benzooxazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-
(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-
ethanone
A. 5-Chloro-2-piperidin-4-yl-benzooxazole.
A flask was charged with 1.35 mL (10 mmol) of methyl isonipicotate,
1.43 g (10 mmol) of 2-amino-4-chlorophenol, and 5 g of
polyphosphoric acid. The flask was then heated to 180.degree. C.
for 5 h. The reaction mixture was then poured into water while
still warm and treated with 50% KOH solution until pH 12. This was
then extracted with CH.sub.2 Cl.sub.2 (3.times.50 mL), then washed
with water (25 mL), brine, dried over Na.sub.2 SO.sub.4, and the
solvent was removed under reduced pressure to give 1.53 g (57%) of
crude product which was used without further purification. MS
(electrospray): exact mass calculated for C.sub.12 H.sub.13
ClN.sub.2 O, 236.07; m/z found, 237.1 [M+H].sup.+.
B.
1-[1-{3-[4-(5-Chloro-benzooxazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3
-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]
-ethanone.
A solution of 130 mg (0.55 mmol) of
5-chloro-2-piperidin-4-yl-benzooxazole was dissolved in 4 mL EtOH
and treated with 100 mg (0.27 mmol) of
1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to
60.degree. C. overnight. The solvent was then removed by rotary
evaporation and the crude product was purified by column
chromatography (silica, 0-10% MeOH/EtOAc) to afford 156 mg (95%) of
a white solid. MS (electrospray): exact mass calculated for
C.sub.30 H.sub.31 ClF.sub.3 N.sub.5 O.sub.3, 601.21. m/z found,
602.2 [M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of
amide rotamers):7.76 (d, J=8.41 Hz, 1H), 7.71 and 7.67 (A and B of
AB quartet, J=8.41 Hz, 2H), 7.65-7.61 (m, 2H), 7.38 (d, J=8.61 Hz,
1H), 7.26 (dd, J=8.61, 1.96, 1H), 4.86 and 4.74 (A and B of AB
quartet, J=15.65 Hz, 1H), 4.64 (br s, 1H), 4.24-4.10 (m, 2.3H),
4.07-3.97 (m, 1.7H), 3.89-3.67 (m, 2H), 3.06-3.00 (m, 1H),
3.00-2.90 (m, 2H), 2.90-2.74 (m, 2H), 2.51-2.38 (m, 3H), 2.25-2.10
(m, 2.3H), 2.20 (s, 1.5H), 2.15 (s, 1.5H), 2.06-1.83 (m, 2.7H).
Example 16
##STR30##
1-[1-{3-[4-(Benzothiazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-
trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-eth
anone
A. 4-(Benzothiazol-2-ylamino)-piperidine-1-carboxylic acid
tert-butyl ester.
To a stirred solution of 300 mg (1.77 mmol) of
2-chlorobenzothiazole in dry DMF (3.5 mL) was added 2.9 g of cesium
carbonate (8.8 mmol) and 535 mg of
tert-butyl-4-hydroxy-1-piperidinecarboxylate (2.66 mmol). The
mixture was stirred at room temperature for 4 h before it was
partitioned between EtOAc (70 mL) and water (30 mL) and separated.
The aqueous layer was further extracted with EtOAc (2.times.50 mL).
The combined organic layers were washed with water (25 mL), brine,
dried over Na.sub.2 SO.sub.4, and the solvent was removed under
reduced pressure. Purification by flash chromatography (silica,
0-15% EtOAc/hexanes) afforded 220 mg (37%) of the desired product
as a white solid. MS (electrospray): exact mass calculated for
C.sub.17 H.sub.23 N.sub.3 O.sub.2 S, 333.15. m/z found, 334.2
[M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz): 7.65 (t, J=7.63
2H), 7.36 (ddd, J=8.41, 7.43, 1.37 Hz, 1H), 7.22 (dt, J=7.63, 1.17
Hz, 1H), 5,36 (m, 1H), 3.79-3.70 (br m, 2H), 3.36 (m, 2H),
2.12-2.04 (br m, 2H), 1.92-1.82 (br m, 2H), 1.48 (s, 9H).
B.
1-[1-{3-[4-(Benzothiazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4
-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-et
hanone.
A solution of 220 mg (0.66 mmol) of
4-(benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl
ester in dichloromethane (2 mL) was treated with trifluoroacetic
acid (0.5 mL) at room temperature overnight. The solvent was then
removed and the crude product dissolved in MeOH and stirred over
100 mg of sodium bicarbonate for 1 h. The solid was filtered off
and the filtrate concentrated. The crude piperidine was then
dissolved in 4 mL EtOH and treated with 220 mg (0.60 mmol) of
1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to
60.degree. C. overnight. The solvent was then removed by rotary
evaporation and the crude product was purified by column
chromatography (silica, 0-10% MeOH/EtOAc) to afford 240 mg (66%) of
a white solid. MS (electrospray): exact mass calculated for
C.sub.30 H.sub.33 F.sub.3 N.sub.6 O.sub.2 S: 598.23. m/z found,
599.3 [M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of
amide rotamers): 7.78 (d, J=8.22 Hz, 1H), 7.72 and 7.68 (A and B of
AB quartet, J=8.41 Hz, 2H), 7.64 (d, J=8.22 Hz, 1H), 7.56 (bd,
J=8.02 Hz, 1H), 7.51 (bd, J=8.02 Hz, 1H), 7.29 (bd, J=7.63 Hz, 1H),
7.08 (bt, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.88 and 4.75 (A and B
of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.23-4.16 (m, 1H),
4.16-4.08 (m, 1H), 4.06-3.98 (m, 2H), 3.92-3.65 (m, 3H), 3.03-2.70
(m, 4H), 2.52-2.41 (m, 3H), 2.26-2.18 (m, 1H), 2.21 (s, 1.5H), 2.16
(s, 1.5H), 2.16-2.08 (m, 2H), 1.66-1.44 (m, 2H).
Example 17
##STR31##
1-[1-{3-[4-(3,5-Dichloro-pyridin-4-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}
-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-y
l]-ethanone
A. 4-(3,5-Dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester.
To a stirred solution of 828 mg (4.12 mmol) of
tert-butyl-4-hydroxy-1-piperidinecarboxylate in 10 mL of dry DMF
was added 165 mg of 60% NaH in mineral oil (4.12 mmol). After
stirring at room temperature for 10 min, 500 mg (2.74 mmol) of
3,4,5-trichloropyridine was added. The mixture was stirred at
80.degree. C. overnight and then partitioned between EtOAc (50 mL)
and water (20 mL) and separated. The aqueous layer was further
extracted with EtOAc (2.times.30 mL). The combined organic layers
were washed with water (25 mL), brine, dried over Na.sub.2
SO.sub.4, and the solvent was removed under reduced pressure.
Column chromatography (silica, 60-100% CH.sub.2 Cl2/hexanes) gave
265 mg (28%) of desired product. MS (electrospray): exact mass
calculated for C.sub.15 H.sub.20 Cl.sub.2 N.sub.2 O.sub.3, 346.09.
m/z found, 369.1 [M+Na].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz):
8.45 (s, 2H), 4.66 (m, 1H), 3.90-3.80 (br m, 2H), 3.26 (m, 2H),
1.96-1.83 (br m, 4H), 1.47 (s, 9H).
B.
1-[1-{3-[4-(3,5-Dichloro-pyridin-4-yloxy)-piperidin-1-yl]-2-hydroxy-propyl
}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-
yl]-ethanone.
A solution of 103 mg (0.30 mmol) of
4-(3,5-dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester in CH.sub.2 Cl.sub.2 (2 mL) was treated with
trifluoroacetic acid (0.5 mL) at room temperature overnight. The
solvent was then removed and the crude product dissolved in MeOH
and stirred over 100 mg of sodium bicarbonate for 1 h. The solid
was filtered off and the filtrate concentrated. The crude
piperidine was then dissolved in 4 mL EtOH and treated with 100 mg
(0.27 mmol) of
1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to
60.degree. C. overnight. The solvent was then removed by rotary
evaporation and the crude product was purified by column
chromatography (silica, 0-10% MeOH/EtOAc) to afford 90 mg (54%) of
a white solid. MS (electrospray): exact mass calculated for
C.sub.28 H.sub.30 Cl.sub.2 F.sub.3 N.sub.5 O.sub.3, 611.17. m/z
found, 612.2 [M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a
mixture of amide rotamers): 8.44 (s, 2H), 7.77 (d, J=8.41 Hz, 1H),
7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65 (d,
J=8.41 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.65 Hz,
1H), 4.66 (br s, 1H), 4.55 (br s, 1H), 4.26-4.08 (m, 2H), 4.08-3.98
(m, 2H), 3.91-3.69 (m, 2H), 3.03-2.92 (m, 1.6H), 2.91-2.85 (m,
0.8H), 2.85-2.75 (m, 1.6H), 2.52-2.40 (m, 3H), 2.35-2.24 (br m,
1H), 2.22 (s, 1.5H), 2.17 (s, 1.5H), 2.03-1.90 (m, 4H).
Example 18
##STR32##
1-[1-{3-[4-(1H-Benzoimidazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-t
rifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-etha
none
A. 2-Piperidin-4-yl-1H-benzoimidazole.
A flask was charged with 1.35 mL (10 mmol) of methyl isonipicotate,
1.0 g (10 mmol) of 1,2-phenylenediamine and 5 g of polyphosphoric
acid. The flask was then heated to 180.degree. C. for 5 h. The
reaction mixture was then poured into water while still warm and
treated with 50% KOH solution until pH 12. This was then extracted
with CH.sub.2 Cl.sub.2 (3.times.50 mL), washed with water (25 mL),
brine, dried over Na.sub.2 SO.sub.4, and the solvent was removed
under reduced pressure to give 530 mg (27%) of crude product which
was used without further purification. MS (electrospray): exact
mass calculated for C.sub.12 H.sub.15 N.sub.3, 201.13. m/z found,
202.1 [M+H].sup.+. .sup.1 H NMR (400 MHz, DMSO-d.sub.6):12.1 (br s,
1H), 7.49 (br m, 1H), 7.38 (br m, 1H), 7.09 (br m, 2H), 3.00 (dt,
J=12.13, 3.33 Hz, 2H), 2.88 (tt, J=11.54, 3.74 Hz, 1H), 2.57 (dt,
J=12.13, 2.35 Hz, 2H), 1.90 (m, 2H), 1.66 (m, 2H).
B.
1-[1-{3-[4-(1H-Benzoimidazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-
trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-eth
anone.
A solution of 83 mg (0.41 mmol) of
2-piperidin-4-yl-1H-benzoimidazole was dissolved in 4 mL EtOH and
treated with 100 mg (0.27 mmol) of
1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to
60.degree. C. overnight. The solvent was then removed by rotary
evaporation and the crude product was purified by column
chromatography (silica, 0-10% MeOH/EtOAc) to afford 55 mg (36%) of
a white solid. MS (electrospray): exact mass calculated for
C.sub.30 H.sub.33 F.sub.3 N.sub.6 O.sub.2, 566.26. m/z found, 567.3
[M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of amide
rotamers):10.66 (br s, 0.5H), 10.57 (br s, 0.5H), 7.73 (bd, J=8.41
Hz, 1H), 7.72-7.63 (m, 3H), 7.60 (bd, J=8.41 Hz, 1H), 7.39-7.32 (m,
1H), 7.23-7.13 (m, 2H), 7.02 (br s, 1), 4.86 and 4.75 (A and B of
AB quartet, J=15.85 Hz, 1.25H), 4.64 (br s, 1H), 4.21-4.06 (m, 2H),
4.06-3.81 (m, 2H), 3.80-3.63 (m, 1H), 3.80-3.69 (m, 1H), 3.00-2.68
(m, 5H), 2.44-2.36 (m, 2H), 2.39-2.23 (m, 2H), 2.19 (s, 1.6H), 2.15
(s, 1.4H), 2.13-2.00 (m, 4H), 2.00-1.80 (m, 2H).
Example 19
##STR33##
6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-
benzo[1,4]oxazin-3-one
A.
5-Methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-1H-pyrazolo[4,3-c]pyridine.
5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazo
lo[4,3-c]pyridine (10.0 g, 29.0 mmol) and epichlorohydrin (24 mL,
307 mmol) were set stirring in DMF (150 mL) containing Cs.sub.2
CO.sub.3 (10.4 g, 31.9 mmol). After stirring at room temperature
for 4 days the mixture was evaporated, brought up in EtOAc and
washed with water. The organics were dried (MgSO.sub.4) and
evaporated to give a light yellow solid. Column chromatography
(silica, 5% acetone/CH.sub.2 Cl.sub.2) gave 4.1 g (35%) of a white
solid. TLC (silica, 5% acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.28.
MS (electrospray): exact mass calculated for C.sub.17 H.sub.18
F.sub.3 N.sub.3 O.sub.3 S, 401.10. m/z found, 402.1 [M+H].sup.+.
.sup.1 H NMR (400 MHz, CDCl.sub.3); 7.84 (d, J=8.3 Hz, 2H), 7.79
(d, J=8.3 Hz, 2H), 4.70-4.62 (m, 3H), 4.25 (d, J=5.4 Hz, 1H),
3.90-3.70 (m, 2H), 3.47 (m, 1H), 3.10-2.9 (m, 6H), 2.65-2.60 (m,
1H).
B. 4-(5-Chloro-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester.
2-Amino-4-chloro-phenol (30.0 g, 209 mmol) and
4-oxo-piperidine-1-carboxylic acid tert-butyl ester (46.0 g, 231
mmol) were set stirring in dichloromethane (600 mL). Sodium
triacetoxyborohydride (58.0 g, 274 mmol) was added in portions over
10 min. Acetic acid (12 mL, 210 mmol) was then added and the
mixture left to stir for 18 h. Saturated NaHCO.sub.3 was added and
the organics seperated. The organics were dried (MgSO.sub.4) and
evaporated to give 56 g (82%) of a light beige solid. TLC (silica,
50% EtOAc/hexanes): R.sub.f =0.66. MS (electrospray): exact mass
calculated for C.sub.16 H.sub.23 ClN.sub.2 O.sub.3, 326.14. m/z
found, 349.1 [M+Na].sup.+. .sup.1 H NMR (400 MHz, DMSO-d.sub.6):
6.70 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.97
(d, J=12.2 Hz, 2H), 3.55-3.50 (m, 1H), 2.93 (br s, 2H), 1.93 (d,
J=11.1 Hz, 2H), 1.48 (s, 9H), 1.35 (d, J=11.2 Hz, 2H).
C.
4-[(5-Chloro-2-hydroxy-phenyl)-ethoxycarbonylmethyl-amino]-piperidine-1-ca
rboxylic acid tert-butyl ester.
4-(5-Chloro-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester (15.6 g, 47.7 mmol) was set stirring in THF (200
mL) and cooled to 5.degree. C. Sodium hydride (1.37 g, 54.2 mmol)
was added in portions over 10 min and the mixture left to stir for
1 h. Ethyl bromoacetate (5.8 mL, 52.3 mmol) was added and the ice
bath removed. After stirring for 20 h the mixture was evaporated,
brought up in EtOc and washed with water. The organics were dried
(MgSO.sub.4) and evaporated to give 22.5 g of a deep red oil. The
oil was purified (silica, 5% acetone/CH.sub.2 Cl.sub.2) to give
12.9 g (65%) of a clear orange liquid. TLC (silica, 5%
acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.43. MS (electrospray): exact
mass calculated for C.sub.20 H.sub.29 ClN.sub.2 O.sub.5, 412.18.
m/z found, 413.2 [M+H].sup.+. .sup.1 H NMR (400 MHz, CDCl.sub.3):
6.75-6.62 (m, 3H), 4.71 (s, 1H), 4.37 (q, J=7.2 Hz, 2H), 4.14 (br
s, 2H), 3.55-3.50 (m, 1H), 3.08 (br t, 2H), 2.14 (m, 2H), 1.65-1.45
(m, 12H), 1.41 (t, J=7.2 Hz, 3H).
D.
4-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxyl
ic acid tert-butyl ester.
4-[(5-Chloro-2-hydroxy-phenyl)-ethoxycarbonylmethyl-amino]-piperidine-1carb
oxylic acid tert-butyl ester (12.9 g, 31.2 mmol) was set stirring
in MeOH (100 mL). A solution of NaOH (2.5 g, 62.5 mmol) in water
(100 mL) was added and the mixture stirred at room temperature for
3 h. The mixture was acidified to pH 2 and MeOH evaporated. The
aqueous layer was extracted twice with EtOAc. The organics were
combined, dried (MgSO.sub.4) and evaporated to give 11 g of a clear
orange oil. The oil was set stirring in CH.sub.2 Cl.sub.2 (150 mL)
and EDC (8.2 g, 42.8 mmol) was added. After 1 h the organics were
washed with 1 N HCl (100 mL), water (100 mL) and dried
(MgSO.sub.4). The solvent was evaporated to give 7.2 g (63%) of a
clear orange solid. TLC (silica, 5% acetone/CH.sub.2 Cl.sub.2):
R.sub.f 0.53. MS (electrospray): exact mass calculated for C.sub.18
H.sub.23 ClN.sub.2 O.sub.4, 366.13; m/z found, 389.1 [M+Na].sup.+.
.sup.1 H NMR (400 MHz, CDCl.sub.3): 7.19 (s, 1H), 7.11-7.00 (m,
2H), 4.60 (s, 2H), 4.50-4.30 (m, 3H), 3.00-2.80 (m, 2H), 2.70-2.60
(m, 2H), 1.86 (d, J=11.4 Hz, 2H), 1.60 (s, 9H).
E. 6-Chloro-4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one.
4-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxyli
c acid tert-butyl ester (7.2 g, 19.6 mmol) was set stirring and a
1:1 TFA/CH.sub.2 Cl.sub.2 solvent mixture was added. After 1 h the
mixture was evaporated under reduced pressure and the resulting red
oil brought up in Et.sub.2 O. A solid formed and was filtered and
air dried to give 7.2 g (96%) of a light beige solid. MS
(electrospray): exact mass calculated for C.sub.13 H.sub.15
ClN.sub.2 O.sub.2, 266.08. m/z found, 267.1 [M+H].sup.+. .sup.1 H
NMR (400 MHz, CD.sub.3 OD): 7.52 (s, 1H), 7.20-7.00 (m, 2H), 4.60
(s, 2H), 4.50-4.40 (m, 1H), 3.65-3.55 (m, 2H), 3.28 (t, J=13.1 Hz,
2H), 3.10-3.00 (m, 2H), 2.15 (d, J=13.9 Hz, 2H).
F.
6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)
-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H
-benzo[1,4]oxazin-3-one.
6-Chloro-4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (252 mg, 0.66
mmol) and
5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-1H-pyrazolo[4,3-c]pyridine (209 mg, 0.52 mmol) were set
stirring in EtOH (10 mL) containing Et.sub.3 N (115 .mu.L, 0.83
mmol) at 70.degree. C. After 2 days the mixture was cooled,
evaporated, brought up in EtOAc and washed with saturated
NaHCO.sub.3. The organics were dried (MgSO.sub.4) and evaporated to
give a clear golden oil. The oil was purified (silica, 50%
acetone/CH.sub.2 Cl.sub.2) to give 191 mg (55%) of a white solid.
TLC (silica, 50% acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.38. MS
(electrospray): exact mass calculated for C.sub.30 H.sub.33
ClF.sub.3 N.sub.5 O.sub.5 S, 667.18. m/z found, 668.2 [M+H].sup.+.
.sup.1 H NMR (400 MHz, CDCl.sub.3): 7.83 (d, J=8.3 Hz, 2H), 7.77
(d, J=8.3 Hz, 2H), 7.21 (s, 1H), 7.10-7.00 (m, 2H), 4.68 (d, J=5.1
Hz, 2H), 4.58 (s, 2H), 4.40-4.10 (m, 4H), 3.90-3.70 (s, 2H),
3.30-3.0 (m, 4H), 3.00 (s, 3H, 2.90-2.70 (m, 2H), 2.65-2.50 (m,
3H), 2.35-2.20 (m, 2H), 1.88 (d, J=11.3 Hz, 2H).
Example 20
##STR34##
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4
-dihydro-1H-quinolin-2-one
A. 3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester.
2-Amino-5-chlorobenzaldehyde (7.58 g, 48.7 mmol) and 36 g (103
mmol) of (carbethoxymethylene)triphenylphosphorane were added in
benzene (300 mL) and heated to reflux for 20 h. The reaction
mixture was cooled and concentrated to give an orange oil. The oil
was brought up in Et.sub.2 O and precipitated appeared. This was
filtered and washed with Et.sub.2 O. The organics were evaporated
to give a clear orange oil. The oil was purified by column
chromatography (silica, 10-40% EtOAc/hexanes) to obtain 10.4 g
(95%) of a yellow solid. MS (electrospray): exact mass calculated
for C.sub.11 H.sub.12 ClNO.sub.2, 225.06. m/z found, 226.1 [M.sup.+
+H]. .sup.1 H NMR (400 MHz, CDCl.sub.3): 7.69 (d, J=15.85 Hz, 1H),
7.30 (d, J=2.54 Hz, 1H), 7.07 (dd, J=6.26 Hz, 2.35 Hz, 1H), 6.60
(d, J=8.61 Hz, 1H), 6.30 (d, J=15.85 Hz, 1H), 4.22 (dd, J=7.24 Hz,
7.24 Hz, 2H), 3.98 (br s, 2H), 1.30 (t, J=7.04 Hz, 3H).
B.
4-[4-Chloro-2-(2-ethoxycarbonyl-vinyl)-phenylamino]-piperidine-1-carboxyli
c acid tert-butyl ester.
3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester (10.4 g, 46
mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (13.8
g, 69 mmol) were set stirring in CH.sub.2 Cl.sub.2 (230 mL). Sodium
triacetoxyborohydride (14.6 g, 69 mmol) was added in portions over
10 min. Acetic acid (1.3 mL, 25 mmol) was then added and the
mixture left to stir. After 18 h saturated NaHCO.sub.3 was added
and the organics separated. The organics were dried over Na.sub.2
SO.sub.4 and concentrated. The residue was purified by column
chromatography (silica, 20-50% EtOAc/hexanes) to obtain 12.4 g
(66%) of a light beige solid. TLC (silica, 25% EtOAc/hexanes):
R.sub.f =0.5. MS (electrospray): exact mass calculated for C.sub.21
H.sub.29 ClN2O.sub.4, 408.18. m/z found, 409.1 [M.sup.+ +H]. .sup.1
H NMR (400 MHz, CDCl.sub.3): 7.64 (d, J=15.65 Hz, 1H), 7.29 (d,
J=2.35 Hz, 1H), 7.14 (dd, J=6.26 Hz, 2.54 Hz, 1H), 6.59 (d, J=9.00
Hz, 1H), 6.28 (d, J=15.65 Hz, 1H), 4.23 (dd, J=7.04 Hz, 7.04 Hz,
2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.46-3.36 (m, 1H), 2.89
(t, J=11.74 Hz, 2H), 2.04-1.95 (m, 2H), 1.44 (s, 9H), 1.42-1.33 (m,
2H), 1.30 (t, J=7.24 Hz, 3H).
C.
4-[4-Chloro-2-(2-ethoxycarbonyl-ethyl)-phenylamino]-piperidine-1-carboxyli
c acid tert-butyl ester.
4-[4-Chloro-2-(2-ethoxycarbonyl-vinyl)-phenylamino]-piperidine-1-carboxylic
acid tert-butyl ester (12.4 g, 30.4 mmol) in EtOAc (150 mL)
containing PtO.sub.2 (1 g) was placed on a Parr hydrogenator at 60
psi H.sub.2. After 18 h the mixture was filtered through celite and
evaporated to give a clear brown liquid. The liquid was purified by
column chromatography (silica, 20-50% EtOAc/hexanes) to obtain 5.7
g (46%) of the title compound. TLC (silica, 25% EtOAc/hexanes):
R.sub.f =0.5. MS (electrospray): exact mass calculated for C.sub.21
H.sub.31 ClN.sub.2 O.sub.4, 410.2. m/z found, 411.2 [M.sup.+ +H].
.sup.1 H NMR (400 MHz, CDCl.sub.3): 7.05 (dd, J=6.06 Hz, 2.54 Hz,
1H), 6.99 (d, J=2.35 Hz, 1H), 6.55 (d, J=8.61 Hz, 1H), 4.13 (dd,
J=7.04 Hz, 3.13 Hz, 2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.72
(t, J=6.26 Hz, 2H), 3.46-3.36 (m, 1H), 2.75 (t, J=7.43 Hz, 2H),
2.60 (t, J=7.04, 2H), 2.04-1.95 (m, 2H), 1.46 (s, 9H), 1.42-1.33
(m, 2H), 1.26 (t, J=7.24 Hz, 3H).
D.
4-[2-(2-Carboxy-ethyl)-4-chloro-phenylamino]-piperidine-1-carboxylic
Acid tert-butyl ester.
4-[4-Chloro-2-(2-ethoxycarbonyl-ethyl)-phenylamino]-piperidine-1-carboxylic
acid tert-butyl ester (5.7 g, 13.9 mmol) was set stirring in MeOH
(40 mL). A solution of NaOH (1.4 g, 34.7 mmol) in water (10 mL) was
added and the mixture stirred at room temperature. After 3 h the
mixture was acidified to pH 7 and MeOH was evaporated. The aqueous
layer was extracted with CH.sub.2 Cl.sub.2 (3.times.100 mL). The
organics were combined, dried over Na.sub.2 SO.sub.4 and
concentrated to afford 3.9 g (73%) of the desired product. TLC
(silica, 50% EtOAc/hexanes): R.sub.f =0.4. MS (electrospray): exact
mass calculated for C.sub.19 H.sub.27 ClN.sub.2 O.sub.4, 382.17;
m/z found, 381.1 [M.sup.31 -H].
E.
4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidine-1-carboxylic
Acid tert-butyl ester.
4-[2-(2-Carboxy-ethyl)-4-chloro-phenylamino]-piperidine-1-carboxylic
acid tert-butyl ester (3.9 g, 10.1 mmol) and EDC (2.9 g, 15.3 mmol)
were set stirring in CH.sub.2 Cl.sub.2 (50 mL) for 2 h. The
reaction mixture was dissolved in CH.sub.2 Cl.sub.2 (150 mL),
washed with water (2.times.50 mL) and brine (1.times.50 mL). The
organic layer was dried over Na.sub.2 SO.sub.4 and concentrated.
The residue was purified by column chromatography (silica, 30-50%
EtOAc/hexanes) to obtain 1.9 g (52%) of the desired product. TLC
(silica, 50% EtOAc/hexanes): R.sub.f =0.67. MS (electrospray):
exact mass calculated for C.sub.19 H.sub.25 ClN.sub.2 O.sub.3,
364.16. m/z found, 365.1 [M.sup.+ +H]. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 7.14-7.08 (m, 2H), 6.98 (d, J=8.61 Hz, 1H), 4.33-3.98
(m, 3H), 2.75 (t, J=7.83 Hz, 4H), 2.55-2.36 (m, 4H), 1.70-1.65 (m,
2H), 1.44 (s, 9H).
F. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one.
4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester (1.2 g, 3.28 mmol) was set stirring in 1:1
TFA/CH.sub.2 Cl.sub.2. After 45 min the mixture was evaporated and
the golden oil brought up in Et.sub.2 O. A solid formed and was
filtered, washed with Et.sub.2 O and air dried to give 1.3 g (93%)
of a white solid. MS (electrospray): exact mass calculated for
C.sub.13 H.sub.17 ClN.sub.2 O, 264.10. m/z found, 265.1 [M.sup.+
+H].
G.
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)
-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3.
4-dihydro-1H-guinolin-2-one.
6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one (270 mg,
0.62 mmol) and
5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-1H-pyrazolo[4,3-c]pyridine (165 mg, 0.41 mmol) were set
stirring in EtOH (10 mL) containing Et.sub.3 N (97 .mu.L, 0.70
mmol) at 80.degree. C. After 16 h the mixture was cooled,
evaporated, brought up in dichloromethane and washed with water.
The organics were dried over Na.sub.2 SO.sub.4 and concentrated.
The residue was purified by column chromatography (silica, 5-10%
MeOH/CH.sub.2 Cl.sub.2) to obtain 205 mg (75%) of a white solid.
TLC (silica, 10% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.75. MS
(electrospray): exact mass calculated for C.sub.31 H.sub.35
ClF.sub.3 N.sub.5 O.sub.4 S, 665.21; m/z found, 666.2 [M.sup.+ +H].
.sup.1 H NMR (CDCl.sub.3, 400 MHz): 7.69 (d, J=8.41 Hz, 2H), 7.62
(d, J=8.41 Hz, 2H), 7.16-7.08 (m, 2H), 7.00 (d, J=9.00 Hz, 1H),
4.52 (dd, J=14.28 Hz, 5.48 Hz, 2H), 4.18 (dd, J=10.56 Hz, 3.13 Hz,
1H), 4.14-4.04 (m, 2H), 4.03-3.96 (m, 1H), 3.72-3.56 (m, 2H),
3.10-2.96 (m, 2H), 2.95-2.86 (m, 2H), 2.85 (s, 3H), 2.75 (t, J=6.26
Hz, 2H), 2.69-2.54 (m, 2H), 2.53-2.47 (m, 2H), 2.44-2.31 (m, 3H),
2.15-2.05 (m, 1H), 1.71-1.62 (m, 2H).
Example 21
##STR35##
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4
-dihydro-1H-quinazolin-2-one
A. Spiro[piperidine-4,2'(1'H)-6'-chloro-3',
4'-dihydro-4'-oxo-quinazoline]-1-carboxylic acid tert-butyl
ester.
To a stirred solution of 2-amino-5-chlorobenzamide (5.67 g, 33.2
mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.62
g, 33.2 mmol) in benzene (70 mL) was added a catalytic amount
(.about.0.3 g) of p-toluenesulfonic acid. The mixture was heated to
reflux for 20 h under a Dean-Stark trap. The resulting suspension
was concentrated. Saturated NaHCO.sub.3 (68 mL) was added. The
mixture was extracted with EtOAc and the precipitated crystal in
the aqueous layer was collected by filtration. The solid was washed
with water and dried to afford 11.22 g (96%) of the desired
product. MS (electrospray): exact mass calculated for C.sub.17
H.sub.22 ClN.sub.3 O.sub.3, 351.13. m/z found, 352.1 [M.sup.+ +H].
.sup.1 H NMR (CD.sub.3 OD, 400 MHz): 7.50 (d, J=2.54 Hz, 1H), 7.13
(dd, J=6.06 Hz, 2.54 Hz, 1H), 6.65 (d, J=8.61 Hz, 1H), 3.56-3.47
(m, 2H), 3.36-3.25 (m, 2H), 1.79-1.66 (m, 4H), 1.32 (s, 9H).
B. 4-(2-Aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic
acid tert-butyl ester.
Spiro[piperidine-4,2'(1'H)-6'-chloro-3',4'-dihydro-4'-oxo-quinazoline]-1-ca
rboxylic acid tert-butyl ester (1 g, 2.8 mmol) and
borane-tetrahydrofurane complex (1.0 M, 9.9 mL, 9.9 mmol) were
added in THF (10 mL) and heated to reflux for 6 h. The reaction
mixture was cooled and poured into ice water. The resulting
suspension was extracted with CH.sub.2 Cl.sub.2 (2.times.100 mL).
The organics were dried and concentrated. The residue was purified
by column chromatography (silica, 5-10% MeOH/CH.sub.2 Cl.sub.2) to
obtain 795 mg (79%) of the product. MS (electrospray): exact mass
calculated for C.sub.17 H.sub.26 ClN.sub.3 O.sub.2, 339.17; m/z
found, 362.1 [M.sup.+ +Na]. .sup.1 H NMR (CDCl.sub.3, 400 MHz):
7.07 (dd, J=6.06 Hz, 2.54 Hz, 1H), 6.97 (d, J=2.54 Hz, 1H), 6.54
(d, J=8.61 Hz, 1H), 3.94-3.70 (m, 4H), 3.48-3.38 (m, 1H), 3.05 (t,
J=11.15 Hz, 2H), 2.68-2.55 (m, 1H), 2.02-1.90 (m, 4H), 1.46 (s,
9H).
C.
4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester.
1,1'-Carbonyldiimidazole (0.51 g, 3.15 mmol) was added to a
solution of
4-(2-aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester (0.79 g, 2.25 mmol) in CH.sub.3 CN (10 mL) over 3
h with stirring at 50.degree. C. The reaction mixture was then
cooled to room temperature and stirred for additional 2 h. The
reaction mixture was dissolved in CH.sub.2 Cl.sub.2 (100 mL),
washed with water (2.times.10 mL), brine (1.times.10 mL). The
organic layer was dried over Na.sub.2 SO.sub.4 and concentrated.
The residue was purified by column chromatography (silica, 30-50%
EtOAc/hexanes) to obtain 0.46 g (63%) of the desired product. TLC
(silica, 50% EtOAc/hexanes): R.sub.f =0.5. MS (electrospray): exact
mass calculated for C.sub.18 H.sub.24 ClN.sub.3 O.sub.3, 365.15.
m/z found, 388.1 [M.sup.+ +Na]. .sup.1 H NMR (CDCl.sub.3, 400 MHz):
7.18 (dd, J=6.26 Hz, 2.54 Hz, 1H), 7.05 (d, J=2.15 Hz, 1H), 6.94
(d, J=9.00 Hz, 1H), 6.29 (s, 1H), 4.32-4.18 (m, 4H), 4.13-4.02 (m,
1H), 2.88-2.71 (m, 2H), 2.64-2.50 (m, 2H), 1.82-1.73 (m, 2H), 1.49
(s, 9H).
D. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-guinazolin-2-one.
4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester (0.52 g, 1.42 mmol) was set stirring in 1:1
TFA/CH.sub.2 Cl.sub.2. After 45 min the mixture was evaporated and
the golden oil brought up in Et.sub.2 O. A solid formed and was
filtered, washed with Et.sub.2 O and air dried to give 0.52 g (97%)
of an off-white solid. MS (electrospray): exact mass calculated for
C.sub.13 H.sub.16 ClN.sub.3 O, 265.10. m/z found, 266.1 [M.sup.+
+H].
E.
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)
-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,
4-dihydro-1H-quinazolin-2-one.
6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (183 mg,
0.42 mmol) and
5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-1H-pyrazolo[4,3-c]pyridine (112 mg, 0.28 mmol) were set
stirring in EtOH (10 mL) containing Et.sub.3 N (66 .mu.L, 0.47
mmol) at 80.degree. C. After 16 h the mixture was cooled,
evaporated, brought up in CH.sub.2 Cl.sub.2 and washed with water.
The organics were dried over Na.sub.2 SO.sub.4 and concentrated.
The residue was purified by column chromatography (silica, 5-10%
MeOH/CH.sub.2 Cl.sub.2) to obtain 141 mg (76%) of a white solid.
TLC (silica, 10% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.6. MS
(electrospray): exact mass calculated for C.sub.30 H.sub.34
ClF.sub.3 N.sub.6 O.sub.4 S, 666.20. m/z found, 667.2 [M.sup.+ +H].
.sup.1 H NMR (CDCl.sub.3, 400 MHz): 7.70 (d, J=7.83 Hz, 2H), 7.63
(d, J=8.02 Hz, 2H), 7.12 (dd, J=6.65 Hz, 2.35 Hz, 1H), 7.01 (br s,
1H), 6.92 (d, J=9.00 HZ, 1H), 5.44 (br s, 1H), 4.54 (dd, J=14.67
Hz, 6.46 Hz, 2H), 4.23-4.08 (m, 4H), 4.05-3.97 (m, 1H), 3.92-3.80
(m, 1H), 3.74-3.57 (m, 2H), 3.14-2.99 (m 2H), 2.97-2.87 (m, 2H),
2.86 (s, 3H), 2.78-2.57 (m, 2H), 2.48-2.32 (m, 3H), 2.10 (t,
J=11.50 Hz 1H), 1.80-1.70 (m, 2H).
Example 22
##STR36##
1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2.lambda..sup.6
-benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-tr
ifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propa
n-2-ol
A. 4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2.lambda..sup.6
-benzo[1,2,6]thiadiazin-1-yl)-piperidine-1-carboxylic acid
tert-butyl ester.
A solution of
4-(2-aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester (678 mg, 2 mmol) and sulfamide (596 mg, 6.2 mmol)
in pyridine (12 mL) was heated to reflux for 6 h. The reaction
mixture was then cooled to room temperature and poured into ice
water (50 mL). The solution was extracted with CH.sub.2 Cl.sub.2
(4.times.100 mL). The organic extracts was dried over Na.sub.2
SO.sub.4 and concentrated. The residue was purified by column
chromatography (silica, 30-50% EtOAc/hexanes) to obtain 767 mg
(96%) of the desired product. TLC (silica, 50% EtOAc/hexanes):
R.sub.f =0.75. MS (electrospray): exact mass calculated for
C.sub.17 H.sub.24 ClN.sub.3 O.sub.4 S, 401.12. m/z found, 400.1
[M.sup.- -H]. .sup.1 H NMR (CDCl.sub.3, 400 MHz): 7.13 (dd, J=6.46
Hz, 2.15 Hz, 1H), 7.00 (d, J=1.96 Hz, 1H), 6.92 (d, J=8.60 Hz, 1H),
5.54 (br s, 1H), 4.35 (s, 2H), 4.11-3.81 (m, 3H), 2.62 (br s, 2H),
1.90-1.66 (m, 4H), 1.34 (s, 9H).
B. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine
2,2-dioxide.
4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2l6-benzo[1,2,6]thiadiazin-1-yl)-piper
idine-1-carboxylic acid tert-butyl ester (767 mg, 1.91 mmol) was
set stirring in 1:1 TFA/CH.sub.2 Cl.sub.2. After 45 min the mixture
was evaporated and the golden oil brought up in Et.sub.2 O. A solid
formed and was filtered, washed with Et.sub.2 O and air dried to
give 730 mg (91%) of an off-white solid. MS (electrospray): exact
mass calculated for C.sub.12 H.sub.16 ClN.sub.3 O.sub.2 S, 301.07.
m/z found, 302.0 [M.sup.+ +H].
C. 1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2.lambda..sup.6
-benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-tr
ifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propa
n-2-ol.
6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine
2,2-dioxide (440 mg, 1.03 mmol) and
5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-1H-pyrazolo[4,3-c]pyridine (415 mg, 1.03 mmol) were set
stirring in EtOH (20 mL) containing Et.sub.3 N (215 .mu.L, 1.54
mmol) at 80.degree. C. After 16 h the mixture was cooled,
evaporated, brought up in CH.sub.2 Cl.sub.2 and washed with water.
The organics were dried over Na.sub.2 SO.sub.4 and concentrated.
The residue was purified by column chromatography (silica, 0-5%
MeOH/CH.sub.2 Cl.sub.2) to obtain 229 mg (32%) of a white solid.
TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.8. MS
(electrospray): exact mass calculated for C.sub.29 H.sub.34
ClF.sub.3 N.sub.6 O.sub.5 S.sub.2, 702.17. m/z found, 703.2
[M.sup.+ +H]. .sup.1 H NMR (CDCl.sub.3, 400 MHz, a mixture of two
rotamers): 7.66 (d, J=8.61 Hz, 2H), 7.60 (d, J=8.61 Hz, 2H), 7.16
(dd, J=6.85 Hz, 1.96 Hz, 1H), 6.98 (s, 1H), 6.95 (d, J=9.00 HZ,
1H), 4.47 (s, 2H), 4.33 (s, 2H), 4.16-3.99 (m, 2H), 3.98-3.90 (m,
1H), 3.89-3.78 (m, 1H), 3.62-3.52 (m, 2H), 3.05-2.95 (m, 1H),
2.93-2.84 (m, 2H), 2.82 (s, 3H), 2.81-2.76 (m, 1H), 2.33 (d, J=6.46
Hz, 2H), 2.25 (t, J=11.24 Hz, 1H), 2.09-1.90 (m, 3H), 1.90-1.78 (m,
2H).
Example 23
##STR37##
4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-pyrido[3,
2-b][1,4]oxazin-3-one
A. 4-(3-Hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid
tert-butyl ester.
To a stirring solution of 4.7 g (0.042 mol) of
2-amino-3-hydroxypyridine and 12.75 g (0.064 mol) of
4-oxo-piperidine-1-carboxylic acid tert-butyl ester in CH.sub.2
Cl.sub.2 /AcOH (150 mL/60 mL) was added 10 g (0.070 mol) of
Na.sub.2 SO.sub.4. After 3.5 h, 9.9 g (0.047) of sodium
triacetoxyborohydride was added in three portions, and the mixture
was stirred at room temperature for 15 h. The reaction was then
quenched with NaHCO.sub.3 (150 mL), extracted with CH.sub.2
Cl.sub.2 (500 mL), washed with NaHCO.sub.3 (2.times.100 mL), and
the combined aqueous layers were extracted with EtOAc (150 mL). The
combined organic layers were dried over Na.sub.2 SO.sub.4,
concentrated, and purified using flash chromatography (silica,
3-10% MeOH/CH.sub.2 Cl.sub.2) to afford 5.9 g (48%) of a beige
powder. MS (electrospray): exact mass calculated for C.sub.15
H.sub.23 N.sub.3 O.sub.3, 293.17. m/z found, 294.2 [M+H].sup.+.
.sup.1 H NMR (400 MHz, CDCl.sub.3): 7.52 (dd, J=5.3 Hz, 1.3 Hz,
1H), 6.79 (dd, J=7.6 Hz, 1.3 Hz, 1H), 6.40 (dd, J=7.6 Hz, 5.3 Hz,
1H), 4.06-3.94 (m, 3H), 3.02-2.86 (m, 2H), 2.72 (br s, 1H),
2.06-1.97 (m, 2H), 1.42 (s, 9H), 1.46-1.28 (m, 2H).
B.
4-(3-Ethoxycarbonylmethoxy-pyridin-2-ylamino)-piperidine-1-carboxylic
Acid tert-butyl ester.
A stirring solution of 1.4 g (0.0048 mol) of
4-(3-hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid
tert-butyl ester was dissolved in THF (24 mL) was cooled to
0.degree. C., and 0.13 g (0.0052 mol) of NaH was added. After 30
min, 0.8 g (0.0052 mol) of ethyl bromoacetate was added, and
reaction was allowed to warm to room temperature and stirred
overnight. Saturated NaHCO.sub.3 (20 mL) was added and the reaction
mixture was partitioned between EtOAc (200 mL) and saturated
NaHCO.sub.3 (75 mL). The organic layer was washed with water (50
mL) and NaCl (50 mL), dried over Na.sub.2 SO.sub.4, and
concentrated to afford 0.9 g (49%) of a white powder. MS
(electrospray): exact mass calculated for C.sub.19 H.sub.29 N.sub.3
O.sub.5, 379.21. m/z found, 380.2 [M+H].sup.+. .sup.1 H NMR (400
MHz, CDCl.sub.3): 7.74 (d, J=5.3 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H),
6.46 (dd, J=7.8 Hz, 5.3 Hz, 1H), 5.05 (d, J=7.33 Hz, 1H), 4.59 (s,
2H), 4.26 (q, J=7.3 Hz, 2H), 4.18-3.92 (m, 3H), 2.97 (t, J=11.6 Hz,
2H), 2.06 (d, J=12.1 Hz, 2H), 1.46 (s, 9H), 1.46-1.34 (m, 2H) 1.29
(t, J=7.3 Hz, 3H).
C.
4-(3-Oxo-2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-yl)-piperidine-1-carboxyli
c acid tert-butyl ester.
To a stirring solution of 0.9 g (0.0023 mol) of
4-(3-ethoxycarbonylmethoxy-pyridin-2-ylamino)-piperidine-1-carboxylic
acid tert-butyl ester in H.sub.2 O/MeOH (1 mL/11 mL) was added 0.05
g (0.0023 mol) of LiOH. After 6 h, the solvent was removed under
reduced pressure. The residue was dissolved in DMF (12 mL) and to
the stirring solution was added 1.82 g (0.0048 mol) of HATU. After
3 h, the reaction was partitioned between EtOAc (250 mL) and
saturated NaHCO.sub.3 (100 mL), and washed with water (3.times.100
mL). The combined aqueous layers were extracted with EtOAc (100
mL). The combined organic layers were washed with brine (100 mL),
dried over Na.sub.2 SO.sub.4, and concentrated to afford 0.37 g
(46%) of a white solid. MS (electrospray): exact mass calculated
for C.sub.17 H.sub.23 N.sub.3 O.sub.4, 333.17. m/z found, 356.1
[M+Na].sup.+. .sup.1 H NMR (400 MHz, CDCl.sub.3): 7.97 (dd, J=4.8
Hz, 1.5 Hz, 1H), 7.25 (dd, J=8.1 Hz, 1.5 Hz, 1H), 6.96 (dd, J=8.1
Hz, 4.8 Hz, 1H), 5.03 (tt, J=11.9 Hz, 4.0 Hz, 1H), 4.55 (s, 2H),
4.13 (d, J=10.9 Hz, 2H), 2.82-2.69 (m, 2H), 2.68 (qd, J=12.4 Hz,
4.0 Hz, 2H), 1.65 (d, J=12.1 Hz, 2H), 1.46 (s, 9H).
D. 4-Piperidin-4-yl-4H-pyrido[3,2-b][1,4]oxazin-3-one.
To a stirring solution of 0.37 g (0.0011 mol) of
4-(3-oxo-2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-yl)-piperidine-1-carboxyli
c acid tert-butyl ester in CH.sub.2 Cl.sub.2 (2.5 mL) was added 2.5
mL of TFA. After 2.5 h, the solvent was removed. The residue was
partitioned between EtOAc (200 mL) and 1 N NaOH (150 mL). The
aqueous layer was extracted with EtOAc (3.times.100 mL) and the
combined organic layers were dried over Na.sub.2 SO.sub.4, and
concentrated to afford 0.24 g (94%) of a white/pink solid. .sup.1 H
NMR (400 MHz, CDCl.sub.3): 7.87 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.25
(dd, J=7.8 Hz, 1.8 Hz, 1H), 6.84 (dd, J=7.8 Hz, 4.8 Hz, 1H),
4.98-4.83 (m, 1H), 4.45 (s, 2H), 3.90 (s, 1H), 3.06 (d, J=8.3 Hz,
2H), 2.65-2.53 (m, 4H), 1.65-1.53 (m, 2H).
E.
4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-pyrido[3
,2-b][1,4]oxazin-3-one.
To a stirring solution of 0.24 g (0.001 mol) of
4-piperidin-4-yl-4H-pyrido[3,2-b][1,4]oxazin-3-one in
EtOH/Dichloroethane (2 mL/2 mL) was added 0.27 g (0.0007 mol) of
5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoro-methyl-phenyl)-4,5,6,7-t
etrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was
heated to 80.degree. C. and stirred for 16 h. The solvent was then
removed under reduced pressure, and the crude product was purified
using flash chromatography (30% acetone/CH.sub.2 Cl.sub.2),
affording 0.42 g (96%) of a white solid. MS (electrospray): exact
mass calculated for C.sub.29 H.sub.33 F.sub.3 N.sub.6 O.sub.5 S,
634.22. m/z found, 635.3 [M+H].sup.+. .sup.1 H-NMR (400 MHz,
CDCl.sub.3): 8.00 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.71 and 7.67 (A and
B of AA'BB' quartet, J.sub.ab =8.4 Hz, 4H), 7.22 (dd, J=7.9 Hz, 1.5
Hz, 1H), 6.94 (dd, J=7.9 Hz, 4.8 Hz, 1H), 4.94 (tt, J=12.1 Hz, 4.0
Hz, 1H) 4.57 and 4.55 (A and B of AB quartet, J.sub.ab =14.5 Hz,
2H), 4.57 (s, 2H), 4.25-4.02 (m, 3H), 3.78-3.61 (m, 2H), 3.16-2.90
(m, 4H), 2.90 (s, 3H), 2.89-2.76 (m, 1H), 2.56-2.43 (m, 3H) 2.23
(t, J=11.2 Hz, 1H), 1.67 (d, J=11.3 Hz, 2H).
Example 24
##STR38##
5-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3
-dihydro-indol-2-one
A. 2-(5-Chloro-2-nitro-phenyl)-malonic acid diethyl ester.
Sodium hydride (2.94 g, 123 mmol) was set stirring in DMSO (100 mL)
and heated to 100.degree. C. Diethyl malonate (17.5 mL, 115 mmol)
in DMSO (30 mL) was added and after 10 min a clear red solution was
obtained. 2,4-Dichloronitrobenzene in DMSO (50 mL) was added. After
1.5 h the mixture was cooled and added to water (1000 mL). The
product was extracted with ether. The organics were dried
(MgSO.sub.4) and evaporated to a clear yellow oil (10 g, 59%). TLC
(silica, 20% EtOAc/hexanes): R.sub.f =0.36. MS (electrospray):
exact mass calculated for C.sub.13 H.sub.14 ClNO.sub.6, 315.05. m/z
found, 338.0 [M+Na].sup.+. .sup.1 H NMR (400 MHz, CDCl.sub.3): 8.05
(d, J=8.7 Hz, 1H), 7.55-7.40 (m, 2H), 5.30 (s, 1H), 4.30 (q, J=7.1
Hz, 4H), 1.31 (t, J=7.1 Hz, 6H).
B. (5-Chloro-2-nitro-phenyl)-acetic acid ethyl ester.
2-(5-Chloro-2-nitro-phenyl)-malonic acid diethyl ester (10.3 g,
32.6 mmol) in DMSO (200 mL) containing LiCl (2.9 g, 68.4 mmol) and
water (0.6 mL, 33.3 mmol) was set stirring and heated to
100.degree. C. After 5 h the mixture was cooled to room temperature
and added to water (750 mL). The product was extracted with two
portions of EtOAc. The organics were combined, washed with water,
dried (MgSO.sub.4) and evaporated to give 5.9 g (75%) of a clear
yellow oil. TLC (silica, 25% EtOAc/hexanes): R.sub.f =0.50. .sup.1
H NMR (400 MHz, CDCl.sub.3): 8.21 (d, J=8.8 Hz, 1H), 7.56 (dd,
J=8.8, 2.3 Hz, 2H), 7.47 (d, J=2.3 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H),
4.12 (s, 2H), 1.38 (t, J=7.1 Hz, 3H).
C. (2-Amino-5-chloro-phenyl)-acetic acid ethyl ester.
(5-Chloro-2-nitro-phenyl)-acetic acid ethyl ester (5.9 g, 24.2
mmol) in benzene (125 mL) containing PtO.sub.2 (500 mg) was placed
on a Parr hydrogenator at 40 psi H.sub.2. After 18 h the mixture
was filtered through celite and evaporated to give a clear brown
liquid. The liquid was purified (silica, 25% EtOAc/hexanes) to give
3.3 g (64%) of a clear golden liquid. TLC (silica, 25%
EtOAc/hexanes): R.sub.f =0.30. MS (electrospray): exact mass
calculated for C.sub.10 H.sub.12 ClNO.sub.2, 213.06. m/z found,
214.1 [M+H].sup.+. .sup.1 H NMR (400 MHz, CDCl.sub.3): 7.20-7.10
(m, 2H), 6.78 (d, J=8.3 Hz, 1H), 4.26 (q, J=7.2, 2H), 1.18 (t,
J=7.1 Hz, 3H).
D.
4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester.
(2-Amino-5-chloro-phenyl)-acetic acid ethyl ester (3.3 g, 15.4
mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.6 g,
23 mmol) were set stirring in CH.sub.2 Cl.sub.2 (50 mL) and sodium
triacetoxyborohydride (4.9 g, 23.1 mmol) was added followed by
acetic acid (3 mL). After 5 days saturated NaHCO.sub.3 was added
and the organics separated. The organics were dried (MgSO.sub.4)
and evaporated to give 7.5 g of a clear golden oil. The oil was
purified (silica, 50% EtOAc/hexanes) to give 3.4 g (63%) of a white
solid. TLC (silica, 25% EtOAc/hexanes): R.sub.f =0.18. MS
(electrospray): exact mass calculated for C.sub.18 H.sub.23
ClN.sub.2 O.sub.3, 350.14. m/z found, 373.1 [M+Na].sup.+. .sup.1 H
NMR (400 MHz, CDCl.sub.3): 7.40-7.30 (m, 2H), 7.00 (d, J=8.4 Hz,
1H), 4.55-4.45 (m, 1H), 4.40 (m, 2H), 3.63 (s, 2H), 2.94 (m, 2H),
2.45-2.30 (m, 2H), 1.82 (m, 2H), 1.62 (s, 9H).
E. 5-Chloro-1-piperidin-4-yl-1,3-dihydro-indol-2-one.
4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester (3.4 g, 9.7 mmol) was set stirring in 1:1
TFA/CH.sub.2 Cl.sub.2. After 45 min the mixture was evaporated and
the golden oil brought up in Et.sub.2 O. A solid formed and was
filtered, washed with Et.sub.2 O and air dried to give 3.4 g (97%)
of a white solid. MS (electrospray): exact mass calculated for
C.sub.13 H.sub.15 ClN.sub.2 O, 250.09. m/z found, 251.1
[M+H].sup.+. .sup.1 H NMR (400 MHz, DMSO-d.sub.6); 7.45 (s, 2H),
7.31 (d, J=8.1 Hz, 1H), 4.55-4.45 (m, 1H), 3.68 (s, 2H), 3.50 (d,
J=12.3, 2H), 3.14 (m, 2H), 2.70-2.55 (m, 2H), 1.87 (d, J=13.1 Hz,
2H).
F.
5-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)
-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,
3-dihydro-indol-2-one.
5-Chloro-1-piperidin-4-yl-1,3-dihydro-indol-2-one (256 mg, 0.70
mmol) and
5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-1H-pyrazolo[4,3-c]pyridine (255 mg, 0.64 mmol) were set
stirring in EtOH (15 mL) containing Et.sub.3 N (107 L, 0.77 mmol)
at 80.degree. C. After 20 h the mixture was cooled, evaporated,
brought up in CH.sub.2 Cl.sub.2 and washed with water. The organics
were dried (MgSO.sub.4) and evaporated to give a clear golden oil.
The oil was purified (silica, 50% acetone/CH.sub.2 Cl.sub.2) to
give 225 mg (54%) of a white solid. TLC (silica, 50%
acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.32. MS (electrospray): exact
mass calculated for C.sub.30 H.sub.33 ClF.sub.3 N.sub.5 O.sub.4 S,
651.19. m/z found, 652.2 [M+H].sup.+. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 7.82 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H),
7.40-7.25 (m, 2H), 7.04 (d, J=8.1 Hz, 2H), 4.66 (d, J=4.0 Hz, 2H),
4.40-4.10 (m, 4H), 4.05-3.70 (m, 3H), 3.59 (s, 2H), 3.30-3.0 (m,
4H), 2.99 (s, 3H), 2.70-2.40 (m, 5H), 2.28 (m, 2H).
Example 25
##STR39##
1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-triflu
oromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-
ol.
A. 5-Chloro-2-(2,2-dimethoxy-ethyl)-phenylamine.
To a stirred solution of 10.3 g (60 mmol) of
4-chloro-2-nitrotoluene in dry DMF (120 mL) was added 16.45 g of
N,N-dimethylformamide dimethylacetal (138 mmol). The mixture was
heated to 140.degree. C. for 18 h after which the solvent was
removed under reduced pressure and the residue diluted with 150 mL
of MeOH and 15.2 mL of chlorotrimethylsilane (120 mmol). The
reaction mixture was then heated to 60.degree. C. overnight.
Methanol was then removed under reduced pressure and the residue
was taken up in EtOH and transferred to a Parr bottle. 100 mg of
10% Platinum on carbon was added and the reaction mixture was put
under 2 atmospheres of hydrogen on a Parr shaker for 8 h. When the
reaction was completed the catalyst was removed by filtration and
the filtrate was concentrated under reduced pressure. The crude
aniline was used without further purification. TLC (silica, 35%
EtOAc/hexanes): R.sub.f =0.4. MS (electrospray): exact mass
calculated for C.sub.10 H.sub.14 ClNO.sub.2, 215.07. m/z found,
216.1 [M+H].sup.+.
B.
4-[5-Chloro-2-(2,2-dimethoxy-ethyl)-phenylamino]-piperidine-1-carboxylic
acid tert-butyl ester.
To a stirred solution of 2 g of
5-chloro-2-(2,2-dimethoxy-ethyl)-phenylamine, (9.27 mmol) in 50 mL
of acetic acid was added 3.7 g of 4-oxo-piperidine-1-carboxylic
acid tert-butyl ester (18.5 mmol). The reaction mixture was allowed
to stir for 1 h at room temperature before the portion wise
addition of 5.9 g of sodium triacetoxyborohydride (27.9 mmol). The
reaction mixture was allowed to stir an additional 5 h before
removing the solvent under reduced pressure. The crude product was
partitioned between CH.sub.2 Cl.sub.2 (250 mL) and water. The
aqueous layer was further extracted with CH.sub.2 Cl.sub.2
(2.times.75 mL). The combined organic layers were then washed with
1 N NaOH (2.times.50 mL), brine, dried over Na.sub.2 SO.sub.4, and
concentrated. Purification by chromatography (silica, 10-25%
EtOAc/hexanes) afforded 1.5 g (71%) of desired product. TLC
(silica, 35% EtOAc/hexanes): R.sub.f =0.49. MS (electrospray):
exact mass calculated for C.sub.20 H.sub.31 ClN.sub.2 O.sub.4,
398.20. m/z found, 399.2 [M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400
MHz): 6.94 (d, J=7.83 Hz, 1H), 6.61 (dd, J=7.83, 2.02 Hz, 1H), 6.57
(d, J=2.02 Hz, 1H), 4.87 (br s, 1H), 4.40 (t, J=5.31 Hz, 1H), 3.97
(br m, 2H), 3.36 (s, 6H), 3.02 (m, 2H), 2.78 (d, J=5.05 Hz, 2H),
2.00 (m, 2H), 1.47 (s, 9H), 1.37 (m, 2H).
C. 6-Chloro-1-piperidin-4-yl-1H-indole.
To a stirred solution of 1.03 g (2.59 mmol) of
4-[5-chloro-2-(2,2-dimethoxy-ethyl)-phenylamino]-piperidine-1-carboxylic
acid tert-butyl ester in 15 mL toluene was added 1.0 g (5.2 mmol)
of p-toluenesulfonic acid. The reaction mixture was heated to
60.degree. C. for 20 min, allowed to cool to room temperature and
quenched with 100 mL of sat. aqueous NaHCO.sub.3 then extracted
with EtOAc (3.times.75 mL). The combined organic layers were washed
with brine, dried over Na.sub.2 SO.sub.4, and concentrated to
afford 590 mg (98%) of the desired product as a pink oil. MS
(electrospray): exact mass calculated for C.sub.13 H.sub.15
ClN.sub.2, 234.09. m/z found, 235.1 [M+H].sup.+. .sup.1 H NMR
(CDCl.sub.3, 400 MHz, a mixture of amide rotamers): 7.52 (d, J=8.34
Hz, 1H), 7.38 (br s, 1H), 7.21 (d, J=3.28 Hz, 1H), 7.06 (dd,
J=8.34, 1.77 Hz, 1H), 6.49 (d, J=3.28 Hz, 1H), 4.24 (m, 1H), 3.30
(m, 2H), 2.85 (dt, J=12.38, 2.53 Hz, 2H), 2.08 (m, 2H), 1.94 (m,
2H).
D.
1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifl
uoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2
-ol.
To a stirred solution of 86 mg (0.21 mmol) of
5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-1H-pyrazolo[4,3-c]pyridine in 4 mL of EtOH was added 50 mg
(0.39 mmol) of 6-chloro-1-piperidin-4-yl-1H-indole. The solution
was heated to 60.degree. C. overnight. The solvent was then removed
by rotary evaporation and the crude product was purified by column
chromatography (silica, gradient elution from 0-5% 2 N NH.sub.3
/MeOH in CH.sub.2 Cl.sub.2) to afford 64 mg (48%) of a white solid.
MS (electrospray), exact mass calculated for C.sub.30 H.sub.33
ClF.sub.3 N.sub.5 O.sub.3 S: 635.19. m/z found, 636.2 [M+H].sup.+.
HPLC (reverse phase conditions 10-90%), t.sub.R =4.88 min. .sup.1 H
NMR (CDCl.sub.3, 400 MHz): 7.72 and 7.67 (A and B of AB quartet,
J=8.80 Hz, 4H), 7.52 (d, J=8.41, 1H), 7.34 (s, 1H), 7.18 (d, J=3.33
Hz, 1H), 7.07 (dd, J=8.41, 1.76 Hz, 1H), 6.50 (d, J=3.33 Hz, 1H),
4.59 and 4.54 (A and B of AB quartet, J=14.48 Hz, 2H), 4.24 (dd,
J=13.69, 2.39 Hz, 1H), 4.21-4.14 (m, 2H), 4.05 (dd, J=13.69, 6.46
Hz, 1H), 3.69 (m, 2H), 3.15 (br d, J=11.54 Hz, 1H), 3.11-2.91 (m,
3H), 2.60-2.48 (m, 3H), 2.28 (dt, J=11.74, 2.15 Hz, 1H), 2.13-1.93
(m, 4H).
Example 26
##STR40##
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzotriazole
To a stirred solution of
3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-propionaldehyde (0.084 g, 0.21 mmol) in
CH.sub.2 Cl.sub.2 (0.5 mL) were added
1-piperidin-4-yl-1H-benzotriazole hydrochloride (Maybridge
Chemicals, 0.050 g, 0.21 mmol), Et.sub.3 N (0.1 mL) and glacial
AcOH (12 L, 0.21 mmol) in that order and stirred for 20 min.
NaBH(OAc).sub.3 (0.058 g, 0.27 mmol) was added and stirred under
nitrogen overnight. Saturated NaHCO.sub.3 (1 mL) was added and
stirred for 30 min. The layers were separated and the aqueous layer
was extracted with CH.sub.2 Cl.sub.2 (3 mL). The combined organic
extracts were washed with brine (3 mL), dried over Na.sub.2
SO.sub.4, and removed under reduced pressure. MPLC of the crude
afforded the desired compound as a white solid (0.098 g, 80%). TLC
(silica, 12% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.44. MS
(electrospray): exact mass calculated for C.sub.28 H.sub.32 F.sub.3
N.sub.7 O.sub.2 S, 587.23. m/z found 588.2 [M+H].sup.+. .sup.1 H
NMR (400 MHz, CDCl.sub.3): 8.00 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.2
Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.41 (dt,
J=0.9, 7.6 Hz, 1H), 7.30 (dt, J=0.9, 7.6 Hz, 1H), 4.59 (br t,
J=11.2 Hz, 1H), 4.50 (s, 2H), 4.10 (t, J=6.7 Hz, 2H), 3.63 (t,
J=5.8 Hz, 2H), 3.00 (br d, J=12.0 Hz, 2H), 2.89 (t, J=5.8 Hz, 2H),
2.86 (s, 3H), 2.38-2.27 (m, 4H), 2.17-1.99 (m, 6H).
Example 27
##STR41##
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-sulfonic acid amide
A.
1-(3-Oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[
4,3-c]pyridine-5-carboxylic acid tert-butyl ester.
Dess-Martin periodinane (1.43 g, 3.36 mmol) was added portion wise
to a stirred solution of
1-(3-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydropyrazo
lo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.30 g, 3.05
mmol) in CH.sub.2 Cl.sub.2 (15 mL) at 0.degree. C. under N.sub.2.
Then the reaction was stirred at 0.degree. C. for 15 min and
allowed to warm to room temperature. After stirring at room
temperature for 1.5 h the reaction was diluted with Et.sub.2 O (50
mL) and saturated NaHCO.sub.3 (15 mL) was added slowly (caution!
gas evolution). Then Na.sub.2 S.sub.2 O.sub.3.5H.sub.2 O (5.31 g,
21.4 mmol) was added and stirred for 30 min. The layers were
separated and the aqueous layer was extracted with Et.sub.2 O
(2.times.30 mL). The combined extracts were washed with brine,
dried (Na.sub.2 SO.sub.4) and concentrated. MPLC (1-10%
MeOH/CH.sub.2 Cl.sub.2) afforded the aldehyde in 79% yield (1.02
g). TLC (silica, 10% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.67. MS
(electrospray) calculated for C.sub.12 H.sub.24 F.sub.3 N.sub.3
O.sub.3, 424.2 ([M+H].sup.+). m/z found, 424.2. .sup.1 H NMR (400
MHz, CDCl.sub.3): 9.82 (s, 1H), 7.65 (br d, J=8.0 Hz, 2H), 7.54 (br
s, 2H), 4.53 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 3.68 (br s, 2H), 3.04
(t, J=6.2 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 1.39 (s, 9H).
B.
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pr
opyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid tert-butyl ester.
To a stirred solution of
1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[
4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.99 g, 23.6
mmol) in CH.sub.2 Cl.sub.2 (20 mL) were added
1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60 g,
25.9 mmol) and glacial AcOH (0.13 mL, 23.6 mmol) in that order and
stirred for 20 min. NaBH(OAc).sub.3 (0.65 g, 30.6 mmol) was added
and stirred under nitrogen for 2 h. Saturated NaHCO.sub.3 (20 mL)
was added and stirred for 30 min, and the layers were separated.
The organic extract was washed with brine, dried over Na.sub.2
SO.sub.4, and concentrated under reduced pressure. MPLC of the
crude afforded the desired compound as a white solid (1.27 g, 85%).
TLC (silica, 7% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.35. MS
(electrospray): exact mass calculated for C.sub.34 H.sub.41 F.sub.3
N.sub.6 O.sub.3, 638.32. m/z found, 639.3 [M+H].sup.+, 661.2
[M+Na].sup.+. .sup.1 H NMR (400 MHz, CDCl.sub.3): 7.81 (br d, J=8.0
Hz, 2H), 7.68 (br s, 2H), 7.25 (dd, J=1.6, 7.5 Hz, 1H), 7.15-7.07
(m, 2H), 7.02(dd, J=1.6, 7.9 Hz, 1H), 4.70 (br s, 2H), 4.38 (tt,
J=4.2, 12.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.45 (s,
3H), 3.07 (d, J=11.6 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2.53-2.42 (m,
2H), 2.44 (t, J=6.7 Hz, 2H), 2.21-2.03 (m, 4H), 1.84 (d, J=12.0 Hz,
2H), 1.52 (s, 9H).
C.
1-Methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-on
e.
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carboxylic acid tert-butyl ester (1.19 g, 1.86 mmol) was
dissolved in trifluoroacetic acid (5 mL) and CH.sub.2 Cl.sub.2 (5
mL) and allowed to stir at room temperature for 2 h. The reaction
mixture was concentrated, diluted with CH.sub.2 Cl.sub.2, and
washed with saturated NaHCO.sub.3. The organic layer was dried over
Na.sub.2 SO.sub.4 and concentrated to afford
1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-on
e (0.955 g, 96%) as a white foam. TLC (silica, 10% MeOH/CH.sub.2
Cl.sub.2): R.sub.f =0.19. MS (electrospray) calculated for C.sub.29
H.sub.33 F.sub.3 N.sub.6 O, 539.3 ([M+H].sup.+). m/z found,
539.3.
D.
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pr
opyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-sulfonic acid (N-t-butoxy carbonyl)amide.
To a solution of chlorosulfonyl isocyanate (0.018 mL, 0.209 mmol)
in CH.sub.2 Cl.sub.2 (0.150 mL) was added 2-methyl-2-propanol
(0.020 mL, 0.209 mmol) and the solution was stirred at room
temperature for 15 min. This solution was then added dropwise to a
solution of
1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-on
e (75 mg, 0.139 mmol) and triethylamine (0.039 mL, 0.279 mmol) in
CH.sub.2 Cl.sub.2 (0.4 mL). An additional 0.15 mL of CH.sub.2
Cl.sub.2 was used to transfer all of the material to the reaction
mixture. The reaction mixture was allowed to stir overnight. Column
chromatography (silica, 2-10% MeOH/CH.sub.2 Cl.sub.2) gave 93 mg
(93%) of the title compound. TLC (silica, 5% MeOH/CH.sub.2
Cl.sub.2): R.sub.f =0.24. MS (electrospray): calculated for
C.sub.34 H.sub.42 F.sub.3 N.sub.7 O.sub.5 S, 718.3 ([M+H].sup.+).
m/z found, 718.3.
E.
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pr
opyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-sulfonic acid amide.
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-sulfonic acid (N-t-butoxy carbonyl)amide (75 mg, 0.105 mmol)
was dissolved in trifluoroacetic acid (0.75 mL) and CH.sub.2
Cl.sub.2 (0.75 mL). The reaction mixture was allowed to stir for 2
h, concentrated, diluted with CH.sub.2 Cl.sub.2 (25 mL) and washed
with saturated NaHCO.sub.3. The organic layer was dried over
Na.sub.2 SO.sub.4, concentrated, and purified by silica gel
chromatography (5-10% MeOH/CH.sub.2 Cl.sub.2) to afford
1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pr
opyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-sulfonic acid amide (15 mg, 23%). MS (electrospray) calculated
for C.sub.29 H.sub.34 F.sub.3 N.sub.7 O.sub.3 S, 618.2
([M+H].sup.+). m/z found, 618.2. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 7.72 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.22
(br s, 1H), 7.04-7.11 (m, 2H), 6.95-7.00 (m, 1H), 5.02 (br s, 1H),
4.53 (s, 1H), 4.08-4.36 (m, 3H), 3.68 (br t, J=5.9 Hz, 2H), 3.38
(s, 3H), 2.95-3.01 (m, 2H), 2.41-2.70 (m, 4H), 2.11-2.34 (m, 4H),
1.52-1.94 (m, 6H).
Example 28
##STR42##
5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-trifluoromethyl-phenyl)-pyr
azol-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one
A.
4-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine
.
To a solution of
4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.5 g,
1.73 mmol) and epichlorohydrin (1.35 mL, 17.3 mmol) in DMF (2 mL)
was added cesium carbonate (0.676 g, 2.07 mmol). The reaction
mixture was allowed to stir for 24 h, diluted with EtOAc and washed
successively with saturated NaHCO.sub.3, water, and brine. The
organic layer was dried over Na.sub.2 SO.sub.4, concentrated and
partially purified by running through a plug of silica gel (5%
acetone/CH.sub.2 Cl.sub.2) to afford
4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine
(0.198 g, 33%) as an unstable oil. TLC (silica, 20%
acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.39. MS (electrospray): exact
mass calculated for C.sub.18 H.sub.14 F.sub.3 N.sub.3 O, 346.1
[M+H].sup.+. m/z found, 346.1.
B.
5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-trifluoromethyl-phenyl)-py
razol-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-on
e.
To a solution of
4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine
(68 mg, 0.197 mmol) and
5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one
(0.055 g, 0.207 mmol) in EtOH (1 mL) was added triethylamine (0.027
mL, 0.197 mmol). The reaction mixture was heated at 80.degree. C.
overnight, concentrated, and purified by column chromatography
(silica, 2-10% MeOH/CH.sub.2 Cl.sub.2) to afford the title compound
(0.026 g, 22%). MS (electrospray): exact mass calculated for
C.sub.31 H.sub.30 ClF.sub.3 N.sub.6 O.sub.2, 611.2 [M+H].sup.+. m/z
found, 611.2. .sup.1 H NMR (400 MHz, CDCl.sub.3): 8.59 (br s, 2H),
8.20 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.61 (d, J=5.9 Hz, 2H), 7.55
(d, J=8.2 Hz, 2H), 7.35 (br s, 1H), 7.09 (dd, J=8.2, 1.8 Hz, 1H),
6.89 (d, J=8.2 Hz, 1H), 4.55-4.60 (m, 2H), 4.39 (d, J=14.2, 4.1 Hz,
1H), 4.31 (d, J=14.2, 6.1 Hz, 1H), 3.80-3.90 (m, 2H), 3.37 (s, 3H),
3.18-3.33 (m, 2H), 3.02-3.17 (m, 2H), 2.77-2.95 (m, 2H), 1.99 (t,
J=12.4 Hz, 2H).
Example 29
##STR43##
4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl
]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one
A. 4-(2-Hydroxy-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester.
2-Aminophenol (15.0 g, 137 mmol) and 4-oxo-piperidine-1-carboxylic
acid tert-butyl ester (27.4 g, 138 mmol) were set stirring in
CH.sub.2 Cl.sub.2 (200 mL) at room temperature. Sodium
triacetoxyborohydride (40.8 g, 193 mmol) was added in portions over
10 min followed by acetic acid (7.8 mL, 136 mmol). After 18 h
saturated NaHCO.sub.3 was added, the organics separated, dried
(MgSO.sub.4) and evaporated to give 36.4 g (91%) of a beige solid.
TLC (silica, 50% EtOAc/hexanes): R.sub.f =0.56. MS (electrospray):
exact mass calculated for C.sub.16 H.sub.24 N.sub.2 O.sub.3,
292.18. m/z found, 315.1 [M+Na].sup.+. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 9.20 (s, 1H), 6.80-6.50 (m, 3H), 6.40 (t, J=6.1 Hz,
1H), 4.30 (d, J=8.7 Hz, 1H), 3.88 (d, J=12.6 Hz, 2H), 3.45-3.35 (m,
1H), 3.00-2.75 (br s, 2H), 1.88 (d, J=10.5 Hz, 2H), 1.40 (s, 9H),
1.30-1.20 (m, 2H).
B. 4-(2-Ethoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic
acid tert-butyl ester.
A mixture of NaH (1.56 g, 65 mmol) in THF (100 mL) was set stirring
and cooled to 5.degree. C.
4-(2-Hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl
ester (17.5 g, 60 mmol) in THF (100 mL) was added dropwise over 30
min. After 2 h ethyl bromoacetate (7.3 mL, 66 mmol) was added.
After stirring at room temperature for 24 h saturated NH.sub.4 Cl
(100 mL) was added and the organics evaporated. The aqueous layer
was extracted with EtOAc (2.times.150 mL). The organics were
combined, dried (MgSO.sub.4) and evaporated to give 24 g of a deep
red liquid. The liquid was purified (silica, 5% acetone/CH.sub.2
Cl.sub.2) to give 21.4 g (94%) of a clear orange liquid. TLC
(silica, 5% acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.48. MS
(electrospray): exact mass calculated for C.sub.20 H.sub.30 N.sub.2
O.sub.5, 378.22. m/z found, 379.2 [M+H].sup.+. .sup.1 H NMR (400
MHz, DMSO): 7.02 (m, 1H), 6.90-6.70 (m, 3H), 4.74 (s, 2H), 4.37 (q,
J=7.1 Hz, 2H), 4.13 (br s, 2H), 3.60-3.50 (m, 1H), 3.08 (m, 2H),
2.16 (m, 2H), 1.60-1.50 (m, 2H), 1.58 (s, 9H), 1.41 (t, J=7.1 Hz,
3H).
C. 4-(2-Carboxymethoxy-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester.
4-(2-Ethoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic
acid tert-butyl ester (21.4 g, 56.5 mmol) was set stirring in MeOH
(150 mL). A solution of NaOH (4.5 g, 112.5 mmol) in water (150 mL)
was added. After 3 h the mixture was acidified to pH 4 with 6 N
HCl. MeOH was removed under reduced pressure and the aqueous layer
extracted with EtOAc (2.times.150 mL). The organics were combined,
dried (MgSO.sub.4) and evaporated to give 20 g (100%) of a brown
solid. MS (electrospray): exact mass calculated for C.sub.18
H.sub.26 N.sub.2 O.sub.5, 350.18. m/z found, 351.2 [M+H].sup.+.
D.
4-(3-Oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic
acid tert-butyl ester.
4-(2-Carboxymethoxy-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester (22 g, 63 mmol) was set stirring in CH.sub.2
Cl.sub.2 (200 mL). EDC (13 g, 68 mmol) was added in one portion.
After 30 min 1 N HCl was added. The organics were seperated, dried
(MgSO.sub.4) and evaporated to give 17 g (81%) of a clear brown
oil. TLC (silica, 5% acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.45. MS
(electrospray): exact mass calculated for C.sub.18 H.sub.24 N.sub.2
O.sub.4, 332.17. m/z found, 259.1 [M-BOC+H].sup.+. .sup.1 H NMR
(400 MHz, CDCl.sub.3): 7.30-7.20 (m, 1H), 7.15-7.10 (m, 3H), 4.61
(s, 2H), 4.60-4.45 (m, 1H), 4.45-4.30 (br s, 2H), 2.88 (t, J=12.5
Hz, 2H), 2.65 (dd, J=12.6, 4.5 Hz, 2H), 1.87 (d, J=12.4 Hz, 2H),
1.60 (s, 9H).
E. 4-Piperidin-4-yl-4H-benzo[1,4]oxazin-3-one.
4-(3-Oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic
acid tert-butyl ester (17 g, 51 mmol) and 1:1 TFA/CH.sub.2 Cl.sub.2
(40 mL) were combined and set stirring. After 45 min the mixture
was evaporated to give a clear brown oil. The oil was set stirring
and Et.sub.2 O was added (300 mL). A solid formed and was filtered,
washed with Et.sub.2 O and air dried to give 16 g (90%) of a light
beige solid. MS (electrospray): exact mass calculated for C.sub.13
H.sub.16 N.sub.2 O.sub.2, 232.12. m/z found, 233.1 [M+H].sup.+.
.sup.1 H NMR (400 MHz, CD.sub.3 OD): 7.44 (dd, J=6.5, 1.4 Hz, 1H),
7.20-7.7.10 (m, 3H), 4.58 (s, 2H), 4.55-4.45 (m, 1H), 4.65-4.55 (m,
2H), 3.27 (dt, J=13.0, 2.3 Hz, 2H), 3.05 (dd, J=12.3, 4.1 Hz, 2H),
2.15 (d, J=13.8 Hz, 2H).
F.
2-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine
.
To a solution of
2-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (200 mg,
0.69 mmol) and epichlorohydrin (0.540 mL, 6.9 mmol) in DMF (2 mL)
was added cesium carbonate (450 mg, 1.38 mmol). The reaction
mixture was allowed to stir for 24 h, diluted with EtOAc, and
washed with saturated NaHCO.sub.3, water, and brine. The organic
layer was dried over Na.sub.2 SO.sub.4, concentrated and purified
by column chromatography (silica, 5% acetone/CH.sub.2 Cl.sub.2) to
afford
2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine
(141 mg, 59%). TLC (silica, 20% acetone/CH.sub.2 Cl.sub.2): R.sub.f
=0.38. MS (electrospray) m/z 347.1 (347.1, calculated for C.sub.17
H.sub.13 F.sub.3 N.sub.4 O, M.sup.+ +H). .sup.1 H NMR (400 MHz,
CDCl.sub.3): 8.51 (dd, J=2.8, 1.8 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H),
8.38 (d, J=12.8 Hz, 1H), 8.01 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.62
(d, J=8.6 Hz, 1H), 4.57 (dd, J=14.7, 3.1 Hz, 1H), 4.21 (dd, J=14.7,
6.1 Hz, 1H), 3.44 (m, 1H), 2.91 (t, J=4.5 Hz, 1H), 2.62 (dd, J=4.0,
2.5 Hz, 1H).
G.
4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-y
l]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one.
To a solution of
2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine
(76 mg, 0.220 mmol) and 4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one
(61 mg, 0.231 mmol) in EtOH (1.1 mL) was added triethylamine (0.031
mL, 0.220 mmol). The reaction mixture was heated to 80.degree. C.
overnight, concentrated, and purified by column chromatography
(silica, 5-10% MeOH/CH.sub.2 Cl.sub.2) to afford
4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-y
l]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one (27 mg, 21%).
TLC (silica, 5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.09. MS
(electrospray): m/z 579.2 (579.2, calculated for C.sub.30 H.sub.29
F.sub.3 N.sub.6 O.sub.3, M.sup.+ +H). .sup.1 H NMR (400 MHz,
CDCl.sub.3): 8.53 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.11 (s,
1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.16 (d, J=5.4
Hz, 1H), 7.00-7.03 (m, 3H), 4.49 (s, 2H), 4.39 (d, J=10.8 Hz, 1H),
3.13 (d, J=11.9 Hz, 1H), 2.96 (d, J=11.9 Hz, 1H), 2.59-2.80 (m,
2H), 2.40-2.55 (m, 3H), 2.17 (t, J=11.9 Hz, 1H),1.77 (d, J=11.9 Hz,
2H).
Example 30
##STR44##
(S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6
,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl
-1,3-dihydro-benzoimidazol-2-one
A. 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester.
1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (7.24 g, 34.1
mmol) and di-tert-butyl dicarbonate (9.12 g, 41.0 mmol) were
combined in DMF (80 mL) and the mixture heated to 40.degree. C.
under N.sub.2 for 17 h. The mixture was allowed to cool, diluted
with EtOAc (800 mL) and washed with saturated NaHCO.sub.3 (150 mL),
H.sub.2 O (3.times.150 mL) and brine (150 mL). The combined aqueous
washes were extracted with EtOAc (2.times.150 mL). The combined
extracts were dried over Na.sub.2 SO.sub.4 and concentrated, to
give
4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester (12.36 g, 94%). TLC (silica, 50%
EtOAc/hexanes): R.sub.f =0.3. MS (electrospray): exact mass
calculated for C.sub.17 H.sub.23 N.sub.3 O.sub.3, 340.16. m/z
found, 340.1 [M+Na].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz):
10.59 (s, 1H), 7.15-7.11 (m, 2H), 7.08-7.02 (m, 2H), 4.49 (tt,
J=8.4, 4.0 Hz, 1H), 4.32 (br s, 2H), 2.89 (br t, J=11.6, 2H), 2.34
(dq, J=12.6, 4.4 Hz, 2H), 1.83 (br d, J=10.5 Hz, 2H) 1.36 (s,
9H).
B. 1-Methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one.
A solution of KHMDS (5.07 g, 25.4 mmol) in THF (40 mL plus a 10 mL
rinse) was added via cannula to a solution of
4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester (6.64 g, 20.2 mmol) in THF (20 mL). The
mixture was stirred for 25 min then iodomethane (5.2 mL, 84 mmol)
was added. The resulting mixture was stirred for 45 min then
diluted with EtOAc (700 mL). The EtOAc was washed with H.sub.2 O
(3.times.200 mL), saturated NaHCO.sub.3 (150 mL) and brine (150
mL). The combined washes were extracted with EtOAc (2.times.150
mL). The combined extracts were dried over Na.sub.2 SO.sub.4 and
concentrated. The crude reaction mixture was purified by column
chromatography (silica, 15-60% EtOAc/hexanes) to give the
methylated adduct (5.21 g, 78%). The purified material was
dissolved in a mixture of CH.sub.2 Cl.sub.2 (40 mL) and TFA (35
mL). The mixture was stirred for 4 h then concentrated in vacuo.
The residue was dissolved in CH.sub.2 Cl.sub.2 (300 mL) and washed
with saturated NaHCO.sub.3 (100 mL). The aqueous layer was
extracted with 5%MeOH/CH.sub.2 Cl.sub.2 (4.times.150 mL). The
combined extracted were dried over Na.sub.2 SO.sub.4 and
concentrated to yield the title compound (3.85 g, containing
inorganic salts) which was suitable for further use. TLC (silica,
5% MeOH/CH.sub.2 Cl.sub.2): R.sub.f =0.1. MS (electrospray): exact
mass calculated for C.sub.13 H.sub.18 N.sub.3 O, 232.14. m/z found
232.1 [M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 Hz): 7.27-7.29 (m,
1H), 7.05-7.12 (m, 2H), 6.99 (dd, J=6.1, 2.1 Hz, 1H), 4.45 (tt,
J=12.5, 4.2 Hz, 1H), 3.42 (s, 3H), 3.27 (dd, J=10.2, 2.1 Hz, 2H),
2.81 (dt, J=2.4, 12.4 Hz, 2H), 2.35 (dq, J=12.5, 4.2 Hz, 2H), 2.26
(br s, 1H), 1.83 (dd, J=12.1, 2.1 Hz, 2H).
C. (R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane.
tert-Butyl-chloro-dimethylsilane (12.9 g, 85.5 mmol) followed by
Et.sub.3 N (19 mL, 136 mmol) was added to a 0.degree. C. solution
of (S)-(+)-glycidol (5.0 g, 67 mmol) in CH.sub.2 Cl.sub.2 (200 mL).
The solution was allowed to warm to 23.degree. C. with stirring
over 17 h. The resulting pink solution was diluted with Et.sub.2 O
(800 mL) and stirred an additional 30 min. The Et.sub.2 O layer was
washed with saturated aqueous NaHCO.sub.3 (200 mL), H.sub.2 O
(2.times.100 mL), brine (100 mL), dried over Na.sub.2 SO.sub.4 and
concentrated. Purification by column chromatography (silica, 5-10%
Et.sub.2 O/hexanes) gave
(R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane (10.01 g, 79%). TLC
(silica, 10% Et.sub.2 O/hexanes): R.sub.f =0.5. .sup.1 H NMR
(CDCl.sub.3, 400 MHz): 3.85 (dd, J=11.9, 3.2 Hz, 1H), 3.66 (dd,
J=11.9, 4.8 Hz, 1H), 3.09 (m, 1H), 2.77 (dd, J=5.0, 4.2 Hz, 1H),
2.64 (dd, J=5.2, 2.7 Hz, 1H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s,
3H).
D.
(R)-3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-p
yrazolo[4,3-c]pyridin-1-yl]-propane-1,2-diol.
Cs.sub.2 CO.sub.3 (1.88 g, 5.77 mmol) was added to a solution of
(R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane (2.72 g, 14.4 mmol)
and
5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyraz
olo[4,3-c]pyridine (1.70 g, 4.81 mmol) in DMF (13 mL). The mixture
was stirred at room temperature for 5 days, then partitioned
between EtOAc (400 mL) and saturated NaHCO.sub.3 (100 mL). The
EtOAc layer was washed with H.sub.2 O (3.times.75 mL) and brine
(100 mL), dried over Na.sub.2 SO.sub.4 and concentrated. The
residue was dissolved in MeOH (125 mL) and treated with CSA (800
mg). The mixture was stirred for 20 h then concentrated. The
residue was re-dissolved in EtOAc (200 mL), washed with saturated
NaHCO.sub.3 (100 mL), dried over Na.sub.2 SO.sub.4 and
concentrated. Purification by column chromatography (silica, 20-60%
acetone/CH.sub.2 Cl.sub.2) gave the corresponding diol (0.78 g,
40%). TLC (25% acetone/CH.sub.2 Cl.sub.2): R.sub.f =0.2. MS
(electrospray): exact mass calculated for C.sub.17 H.sub.21 F.sub.3
N.sub.3 O.sub.4 S, 420.11. m/z found, 420.1 [M+H].sup.+. .sup.1 H
NMR (CD.sub.3 OD/CDCl.sub.3, 400 MHz): 7.74 and 7.67 (A and B of
AA'BB', J.sub.ab =8.3 Hz, 4H), 4.52 (s, 2H), 4.23 (dd, J=13.0, 3.0
Hz, 1H), 4.04-4.11 (m, 2H), 3.64 (t, J=5.9 Hz, 2H), 3.52 and 3.57
(A and B of ABX, J.sub.ab =11.4, J.sub.ax =4.8, J.sub.bx =4.9 Hz,
2H), 2.98 (m, 2H), 2.91 (s, 3H).
E.
(R)-5-Methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,
7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.
PpTs (271 mg, 1.1 mmol) and
(R)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-p
yrazolo[4,3-c]pyridin-1-yl]-propane-1,2-diol (317 mg, 0.756 mmol)
were combined in trimethylorthoacetate (30 mL). The mixture was
stirred for 18 h then diluted with EtOAc (125 mL), washed with
saturated NaHCO.sub.3 (2.times.50 mL), brine (50 mL), dried over
Na.sub.2 SO.sub.4 and concentrated. Purification by chromatography
(silica, 100% EtOAc) gave the corresponding orthoacetate (313 mg,
0.678 mmol). The purified orthoacetate was dissolved in CH.sub.2
Cl.sub.2 (2.25 mL), cooled to 0.degree. C., and treated with MeOH
(25 .mu.L) and AcBr (110 .mu.L, 1.48 mmol). The mixture was allowed
to warm over 3 h, then partitioned between EtOAc (50 mL) and
saturated NaHCO.sub.3 (20 mL). The EtOAc layer was washed with
saturated NaHCO.sub.3 (2.times.20 mL). The combined washes were
extracted with EtOAc (3.times.20 mL). The combined extracts were
dried over Na.sub.2 SO.sub.4 and concentrated. The residue was
dissolved in EtOH (40 mL) and treated with KOEt (1.0 mL, 40 wt %
solution in EtOH). After 1 h the mixture was concentrated to ca. 20
mL and worked up as above. Purification by column chromatography
(silica, 100% EtOAc) gave the epoxide (189 mg, 62%). TLC (100%
EtOAc): R.sub.f =0.35. MS (electrospray): exact mass calculated for
C.sub.17 H.sub.19 F.sub.3 N.sub.3 O.sub.3 S, 402.10. m/z found,
402.1 M+H].sup.+. .sup.1 H NMR (CDCl.sub.3, 400 MHz): 7.72 and 7.67
(A and B of AA'BB', J.sub.ab =8.3 Hz, 4H), 4.57 and 4.53 (A and B
of AB, J.sub.ab =12.9 Hz, 2H), 4.52 (dd, J=15.2, 2.7 Hz, 1H), 4.12
(dd, J=15.2, 5.4 Hz, 1H), 3.67 (m, 2H), 3.36 (m, 1H), 2.92 (m, 2H),
2.88 (s, 3H), 2.85 (dd, J=4.4, 4.3 Hz, 1H), 2.49 (dd, J=4.6, 2.6
Hz, 1H).
F.
(S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,
6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methy
l-1,3-dihydro-benzoimidazol-2-one.
A solution of
(R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,
7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (134 mg, 0.334 mmol) and
1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (110 mg,
0.476 mmol) in EtOH (0.8 mL) and dichloroethane (0.8 mL) was heated
to 80.degree. C. for 18 h. The mixture was then concentrated and
the residue purified by column chromatography (silica, 0-50%
acetone/CH.sub.2 Cl.sub.2) to give the title compound (134 mg,
86%). TLC (20% acetone/CH.sub.2 Cl.sub.2) R.sub.f =0.3. MS
(electrospray): calculated for C.sub.30 H.sub.36 F.sub.3 N.sub.6
O.sub.4 S, [M+H].sup.+ 633.24. m/z found, 633.3. .sup.1 H NMR
(CDCl.sub.3, 400 MHz): 7.72 and 7.66 (A and B of AA'BB', J.sub.ab
=8.3 Hz, 4H), 7.15 (dd, J=7.0, 1.7 Hz, 1H ), 7.08 (m, 2H), 6.98
(dd, J=6.6, 1.8 Hz, 1H), 4.60 and 4.55(A and B of AB, J.sub.ab
=14.5 Hz, 2H), 4.34 (m, 1H), 4.23 (dd, J=13.8, 2.8 Hz, 1H), 4.15
(m, 1H), 4.23 (dd, J=13.8, 6.6 Hz, 1H), 3.71 (m, 2H), 3.40 (s, 3H),
3.08 (m, 2H), 2.96 (m, 2H), 2.89 (s, 3H), 2.56-2.36 (m, 4H), 2.23
(d, J=11.6 Hz, 1H, 1.81 (m, 2H).
Example 31
##STR45##
(S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluorometh
yl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidi
n-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
A. 4-(6-Chloro-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic
acid tert-butyl ester.
A stirring solution of 20 g (0.10 mol) of
2,6-dichloro-3-nitro-pyridine in DMF (245 mL) was cooled to
0.degree. C. After 5 min, 9.87 g (0.05 mol) of
4-amino-piperidine-1-carboxylic acid tert-butyl ester and 6.8 g
(0.05 mol) of K.sub.2 CO.sub.3 were added, resulting in a
suspension. The mixture was allowed to stir for 5 h at 0.degree. C.
The mixture was then partitioned between water (300 mL) and EtOAc
(400 mL). The aqueous layer was then extracted with EtOAc
(5.times.400 mL). The organic layer was dried over anhydrous
Na.sub.2 SO.sub.4, and concentrated to give a brown oil. The
product was purified using silica gel chromatography (silica, 100%
CH.sub.2 Cl.sub.2, then 10% EtOAc/hexanes) to afford 8.99 g (51%)
of the desired product as a bright yellow solid. MS (electrospray):
exact mass calculated for C.sub.15 H.sub.21 ClN.sub.4 O.sub.4,
356.13. m/z found, 379.1 [M+Na].sup.+. .sup.1 H NMR (400 MHz,
CDCl.sub.3): 8.36 (d, J=8.4 Hz, 1H), 8.27 (d, J=7.3 Hz, 1H), 6.62
(d, J=8.4 Hz, 1H), 4.38-4.26 (m, 1H), 4.14-3.96 (m, 2H), 3.01 (t,
J=11.6 Hz, 2H), 2.05 (dd, J=12.4 Hz, 3.03 Hz, 2H), 1.58-1.44 (m,
2H), 1.47 (s, 9H).
B.
4-(6-Dimethylamino-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic
acid tert-butyl ester.
To a stirring solution of 6 g (0.016 mol) of
4-(6-chloro-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid
tert-butyl ester in MeOH/CH.sub.2 Cl.sub.2 (84 mL/15 mL) was added
2.2 g (0.05 mol) of dimethylamine in THF (25 mL). The reaction
mixture was stirred at room temperature for 16 h, and was then
concentrated. The crude product was then dissolved in CH.sub.2
Cl.sub.2 (400 mL) and washed with saturated NaHCO.sub.3
(2.times.200 mL). The washes were combined and extracted with EtOAc
(100 mL). The combined organic layers were dried over Na.sub.2
SO.sub.4 and concentrated to afford 6.1 g (99%) of the desired
product as a bright yellow solid. MS (electrospray): exact mass
calculated for C.sub.17 H.sub.27 N.sub.5 O.sub.4, 365.21; m/z
found, 388.19 [M+Na].sup.+. .sup.1 H NMR (400 MHz, CDCl.sub.3):
8.74 (d, J=7.07 Hz, 1H), 8.18 (d, J=9.4 Hz, 1H), 5.97 (d, J=7.3 Hz,
1H), 4.28-4.16 (m, 1H), 4.07-3.93 (m, 2H), 3.17 (s, 6H), 3.01 (t,
J=11.9 Hz, 2H), 2.05 (dd, J=12.4 Hz and 3.03 Hz, 2H), 1.60-1.50 (m,
2H), 1.47 (s, 9H).
C.
4-(5-Dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-
piperidine-1-carboxylic acid tert-butyl ester.
A stirring solution of 5.3 g (0.014 mol) of
4-(6-dimethylamino-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic
acid tert-butyl ester in methanol/EtOAc (73 mL/15 mL) was degassed.
10% Pd/C (1.17 g, 0.5 mmol) was added as a suspension in EtOH (5
mL), followed by ammonium formate (4.5 g, 0.073 mol). The mixture
was stirred at room temperature for 3 h. The reaction mixture was
then filtered through celite and the filtrate was concentrated,
giving a purple oil. The residue was then dissolved in THF (73 mL),
and 11.7 g (0.073 mol) of CDl was added, and the reaction was
heated to 98.degree. C. and stirred for 16 h. The mixture was then
cooled and concentrated. The crude product was then partitioned
between EtOAc (800 mL) and NaHCO.sub.3 (100 mL), and the organic
layer was washed with water (5.times.100 mL) and NaCl (100 mL). The
combined aqueous layers were back-extracted with EtOAc (150 mL).
The resulting organic layers were combined and dried over Na.sub.2
SO.sub.4 and concentrated. The residue (2.4 g) was dissolved in THF
(73 mL). To this stirring solution was added KHMDS (3.46 g, 0.017
mol) and iodomethane (10.3 g, 0.072 mol), and the mixture was
allowed to stir for 20 min. The solvent was then concentrated, and
the crude product was partitioned between EtOAc (600 mL) and
NaHCO.sub.3 (200 mL). The organic layer was washed with NaHCO.sub.3
(150 mL), dried over Na.sub.2 SO.sub.4, and concentrated.
Purification using flash chromatography (silica, 80% EtOAc/hexanes)
afforded 2.4 g (67% yield, 3 steps, based upon using 2/3 material
at methylation stage) of desired product as a white solid. MS
(electrospray): exact mass calculated for C.sub.19 H.sub.29 N.sub.5
O.sub.3, 375.23. m/z found, 276.17 [M+H-100].sup.+. .sup.1 H NMR:
(400 MHz, CDCl.sub.3): 7.02 (d, J=8.6 Hz, 1H), 6.15 (d, J=8.6 Hz,
1H), 4.46 (tt, J=12.0 Hz and 4.0 Hz, 1H), 4.38-4.11(m, 2H), 3.33
(s, 3H), 3.01 (s, 6H), 2.95-2.73 (m, 2H), 2.73-2.55 (m, 2H),
1.77-1.61 (m, 2H), 1.47 (s, 9H).
D.
5-Dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridi
n-2-one.
To a stirring solution of 1.07 g (0.0028 mol) of
4-(5-dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-
piperidine-1-carboxylic acid tert-butyl ester in CH.sub.2 Cl.sub.2
(7 mL) was added 7 mL of TFA. After 35 min, the solvent was
removed. The residue was partitioned between EtOAc (200 mL) and 1 N
NaOH (150 mL). The aqueous layer was extracted with EtOAc
(3.times.100 mL) and the combined organic layers were dried over
Na.sub.2 SO.sub.4 and concentrated to afford 0.74 g (96%) of
5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridi
n-2-one as a white/pink solid. .sup.1 H NMR (400 MHz, CDCl.sub.3):
6.95 (d, J=8.3 Hz, 1H), 6.08 (d, J=8.3 Hz, 1H), 4.35 (tt, J=12.1
Hz, 4.0 Hz, 1H), 3.25 (s, 3H), 3.14 (d, J=12.4 Hz, 2H) 2.97 (s,
6H), 2.66 (td, J=12.9 Hz, 1.3 Hz, 2H), 2.53 (qd, J=12.4 Hz, 4.0 Hz,
2H), 1.69 (d, J=11.9 Hz, 2H).
E.
(S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromet
hyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperid
in-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.
To a stirring solution of 0.24 g (0.0009 mol) of
5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridi
n-2-one in EtOH/Dichloroethane (1.5 mL/1.5 mL) was added 0.23 g
(0.0005 mol) of
(R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,
7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was
heated to 80.degree. C. and stirred for 16 h and concentrated. The
crude product was then dissolved in CH.sub.2 Cl.sub.2 (40 mL) and
purified using flash chromatography (0-6% MeOH/CH.sub.2 Cl.sub.2)
affording 0.38 g (97%) of the desired product as a white solid. MS
(electrospray): exact mass calculated for C.sub.31 H.sub.39 F.sub.3
N.sub.8 O.sub.4 S, 676.28. m/z found, 677.28 [M+H].sup.+. .sup.1 H
NMR (400 MHz, CDCl.sub.3):7.71 and 7.67 (A and B of AA'BB' quartet
J.sub.ab =8.3 Hz, 4H), 7.03 (d, J=8.6 Hz, 1H), 6.16 (d, J=8.6 Hz,
1H), 4.58 and 4.56 (A and B of AB quartet, J.sub.ab =14.5 Hz, 2H),
4.36 (tt, J=12.1 Hz, 4.04 Hz, 1H), 4.25-4.01 (m, 4H), 3.77-3.60 (m,
2H), 3.33 (s, 3H), 3.16-3.04 (m, 2H), 3.03 (s, 6H), 2.99-2.90 (m,
2H), 2.88 (s, 3H), 2.77 (qd, J=12.1 Hz, 3.54 Hz, 2H), 2.56-2.42 (m,
3H), 2.21 (t, J=11.6 Hz, 1H), 1.75 (d, J=11.6 Hz, 2H).
Example 32
##STR46##
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one
Example 33
##STR47##
1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2
-one
Example 34
##STR48##
3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-pipe
ridin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid amide
Example 35
##STR49##
6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-b
enzoimidazol-2-one
Example 36
##STR50##
3-(3,4-Dichloro-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1
-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-c
arboxylic acid amide
Example 37
##STR51##
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-d
ihydro-benzoimidazol-1-yl]-acetonitrile
Example 38
##STR52##
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-d
ihydro-benzoimidazol-1-yl]-acetic acid ethyl ester
Example 39
##STR53##
5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-m
ethyl-1,3-dihydro-benzoimidazol-2-one
Example 40
##STR54##
1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-
1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idine-5-carboxylic acid amide
Example 41
##STR55##
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl
-1,3-dihydro-benzoimidazol-2-one
Example 42
##STR56##
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-
imidazo[4,5-b]pyridin-2-one
Example 43
##STR57##
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-
imidazo[4,5-b]pyridin-2-one
Example 44
##STR58##
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydro-imidazo[4
,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-
c]pyridine-5-carboxylic acid amide
Example 45
##STR59##
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-
methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
Example 46
##STR60##
5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-p
henyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-
yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
Example 47
##STR61##
6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-i
ndol-2-one
Example 48
##STR62##
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-
1H-quinolin-2-one
Example 49
##STR63##
4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-
one
Example 50
##STR64##
4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4
]oxazin-3-one
Example 51
##STR65##
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazo
lin-2-one
Example 52
Cathepsin S Inhibition Assay.
Recombinant human cathepsin S (CatS) was expressed in the
baculovirus system and purified in one step with a
thiopropyl-sepharose column. 10-L yielded .about.700 mg of CatS and
N-terminal sequencing confirmed identity. The assay is run in 100
mM sodium acetate pH 5.0 containing 1 mM DTT and 100 mM NaCl. The
substrate for the assay is
The K.sub.m for the substrate is around 5 .mu.M but the presence of
substrate inhibition makes kinetic analysis difficult. With 20
.mu.M substrate the assay rate is linear over the range of 1-8 ng
CatS in 100 .mu.l reaction. Using 2 ng/well of CatS, the production
of product is linear and yields .about.7-fold signal after 20 min
with only 20% loss of substrate. Primary assays are run by
quenching the reaction after 20 min with 0.1% SDS and then
measuring the fluorescence. For other assays, measurements are
taken every min for 20 min. The rate is calculated from the slope
of the increase and the percent inhibition is calculated from this
(See Tables 1, 2 and 3 below).
TABLE 1 EXAMPLE IC.sub.50 (.mu.M) 1 0.73 2 0.07 3 0.28 4 0.19 5
1.16 6 0.19 7 0.26 8 0.04 9 0.10 10 0.09 11 0.03 12 0.62 13 0.37 14
0.29 15 0.23 16 0.30 17 1.30 18 0.25 19 0.02 20 0.01 21 0.02 22
0.03 23 0.08 24 0.03 25 0.23 26 0.18 27 0.09 28 0.89 29 0.78 30
0.04 31 0.07
TABLE 2 EXAMPLE IC.sub.50 (.mu.M) 32 0.06 33 0.01 34 0.02 35 0.03
36 0.04 37 0.05 38 0.02 39 0.04 40 0.04 41 0.03 42 0.08 43 0.02 44
0.03 45 0.02 46 0.03 47 0.04 48 0.02 49 0.02 50 0.02 51 0.02
Example 101
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-octahydro-benzoimidazo
l-2-one
Example 102
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-octahydro-benzoimidazol-2-
one
Example 103
Acetic acid
1-(1-{3-[5-acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl ester
Example 104
Methanesulfonic acid
1-(1-{3-[3-(4-bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl
ester
Example 105
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-one
Example 106
1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(
3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxyli
c acid amide
Example 107
1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(
3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxyli
c acid methylamide
Example 108
Acetic acid
1-(1-{3-[5-acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-
c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl
ester
Example 109
Methanesulfonic acid
1-(1-{3-[3-(3,4-dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyra
zolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl
ester
Example 110
1-[1-{3-[4-(3,5-Dichloro-pyridin-4-ylamino)-piperidin-1-yl]-2-hydroxy-propy
l}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5
-yl]-ethanone
Example 111
1-[1-{3-[4-(Benzooxazol-2-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-tri
fluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethano
ne
Example 112
1-[1-{3-[4-(Benzooxazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-t
rifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-etha
none
Example 113
1-(4-Benzooxazol-2-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluorome
thyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol
Example 114
1-(4-Benzothiazol-2-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluorom
ethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol
Example 115
1-{3-[4-(5-Methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-
propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyri
dine-5-carboxylic acid amide
Example 116
N-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-N-(3-chloro-phenyl)-b
enzamide
Example 117
4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-
one
Example 118
4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]
oxazin-3-one
Example 119
3-(4-Bromo-phenyl)-1-{3-[4-(5-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-y
l)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-car
boxylic acid amide
Example 120
4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one
Example 121
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-o
ne
Example 122
3-(4-Bromo-phenyl)-1-{3-[4-(6-ethanesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]ox
azin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid amide
Example 123
4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-on
e
Example 124
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]ox
azin-3-one
Example 125
1-[1-[3-(4-Benzothiazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-chloro-
3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone
Example 126
1-[1-[3-(4-Benzothiazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluo
romethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone
Example 127
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1
H-quinolin-2-one
Example 128
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-
1H-quinolin-2-one
Example 129
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinoli
n-2-one
Example 130
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1
H-quinazolin-2-one
Example 131
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl
)-6-chloro-3,4-dihydro-1H-quinazolin-2-one
Example 132
1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]p
yridin-1-yl]-3-[4-(6-chloro-2,2-dioxo-3,4-dihydro-2H-2.lambda..sup.6
-2,1,3-benzothiadiazin-1-yl)-piperidin-1-yl]-propan-2-ol
Example 133
1-[4-(6-Chloro-2,2-dioxo-2,3-dihydro-2.lambda..sup.6
-2,1,3-benzothiadiazol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-tri
fluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan
-2-ol
Example 134
1-[1-{3-[4-(6-Chloro-2,2-dioxo-2,3-dihydro-2.lambda..sup.6
-2,1,3-benzothiadiazol-1-yl)-piperidin-piperidin-1-yl]-2-hydroxy-propyl}-3
-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]
-ethanone
Example 135
4-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-1,4-benzoxazin-3-on
e
Example 136
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinoli
n-2-one
Example 137
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinoli
n-2-one
Example 138
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-on
e
Example 139
4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-o
ne
Example 140
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinol
in-2-one
Example 141
1-{2-Hydroxy-3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-prop
yl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine
-5-carboxylic acid tert-butyl ester
Example 142
1-{2-Hydroxy-3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-p
ropyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
ine-5-carboxylic acid tert-butyl ester
Example 143
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-4H-1,4-benzox
azin-3-one
Example 144
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one
Example 145
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one
Example 146
1-{3-[4-(2-Oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-3-(4-t
rifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxy
lic acid tert-butyl ester
Example 147
1-{3-[4-(3-Oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-3-(
4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carb
oxylic acid tert-butyl ester
Example 148
6-Chloro-4-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridine-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzo
xazin-3-one
Example 149
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-chloro-4H-1,4-benzoxazin-3-one
Example 150
4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one
Example 151
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one
Example 152
4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one
Example 153
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one
Example 154
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-o
ne
Example 155
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-on
e
Example 156
1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-o
ne
Example 157
1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-
indol-2-one
Example 158
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-o
ne
Example 159
1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one
Example 160
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one
Example 161
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-
indol-2-one
Example 162
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3
-dihydro-indol-2-one
Example 163
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-
indol-2-one
Example 164
5-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-i
ndol-2-one
Example 165
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-on
e
Example 166
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-i
ndol-2-one
Example 167
4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-pyrido[3,2-b]-1,4-o
xazin-3-one
Example 168
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dihydro-
4,1-benzoxazepin-2-one
Example 169
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,4-dihydro-
3,1-benzoxazin-2-one
Example 170
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzox
azin-2-one
Example 171
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dihydro-
4,1-benzoxazepin-2-one
Example 172
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,4-dihydro-
3,1-benzoxazin-2-one
Example 173
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzox
azin-2-one
Example 174
1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(5-nitro-2,3-dihydro-indo
l-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5
-yl)-ethanone
Example 175
1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(6-nitro-2,3-dihydro-indo
l-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5
-yl)-ethanone
Example 176
1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-methyl-2,3-dihydro-ind
ol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-
5-yl)-ethanone
Example 177
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-
1H-quinazolin-2-one
Example 178
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazo
lin-2-one
Example 179
1(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazo
lin-2-one
Example 180
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one
Example 181
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one
Example 182
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1-(3-chloro-phenyl)-3
-methyl-urea
Example 183
1-[3-(4-Benzotriazol-1-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(3,4-dichloro
-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester
Example 184
1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(
3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxyli
c acid tert-butyl ester
Example 185
5-Chloro-1-(1-{3-[3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one
Example 186
1-{3-[4-(5-Methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]p
ropyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
ine-5-carboxylic acid tert-butyl ester
Example 187
3-(4-Bromo-phenyl)-1-{3-[4-(5-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-y
l)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-car
boxylic acid tert-butyl ester
Example 188
3-(4-Bromo-phenyl)-1-{3-[4-(6-ethanesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]ox
azin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid tert-butyl ester
Example 187
1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-1-yl]-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin
-1-yl]-propan-2-ol
Example 190
5-Methyl-4-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one
Example 191
4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one
Example 192
4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-one
Example 193
1-{3-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-3-(
4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine
Example 194
3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1
-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester
Example 195
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-p
iperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxy
lic acid tert-butyl ester
Example 196
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl
)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carb
oxylic acid tert-butyl ester
Example 197
1-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one
Example 198
3-(4-Bromo-phenyl)-1-{3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidi
n-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester
Example 199
1-(1-{2-Hydroxy-3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one
Example 200
4-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one
Example 201
1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one
Example 202
4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one
Example 203
1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one
Example 204
4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one
Example 205
4-(1-{2-Hydroxy-3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one
Example 206
1-(3-(3,4-Difluoro-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-1-yl]
-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 207
1-[1-{3-[4-(5-Bromo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propy
l}-3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5
-yl]-ethanone
Example 208
1-(1-{3-[5-Acetyl-3-(3,4-difluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one
Example 209
1-[1-{3-[4-(5-Bromo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propy
l}-3-(3,4-difluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-
ethanone
Example 210
1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one
Example 211
1-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one
Example 212
1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]
-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one
Example 213
1-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenylamino)-piperidin-1-yl]-2-hyd
roxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 214
N-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-N-(3-chloro-phenyl)-a
cetamide
Example 215
1-(4-Benzoimidazol-1-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluoro
methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol
Example 216
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenylamino)-piperidin-
1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 217
1-(3-(4-Chloro-phenyl)-1-{3-[4-(2-fluoro-phenylamino)-piperidin-1-yl]-2-hyd
roxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 218
1-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-phenylamino-piperidin-1-yl)-propyl
]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone
Example 219
1-(3-(4-Chloro-phenyl)-1-{3-[4-(4-chloro-phenylamino)-piperidin-1-yl]-2-hyd
roxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 220
1-[1-{3-[4-(4-Bromo-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-chl
oro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone
Example 221
4-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile
Example 222
1-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-p-tolylamino-piperidin-1-yl)-propy
l]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone
Example 223
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenylamino)-piperidin-
1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 224
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(3-methoxy-phenylamino)-piperidin-
1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 225
1-(3-(4-Chloro-phenyl)-1-{3-[4-(3,5-dimethoxy-phenylamino)-piperidin-1-yl]-
2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 226
1-[1-{3-[4-(5-Chloro-2-methyl-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl
}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethan
one
Example 227
1-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenylamino)-piperidin-1-yl]-2-hyd
roxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 228
[2-(1-{3-[3-(4-Bromo-phenyl)-5-carbamoyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]
pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic
acid methyl ester
Example 229
[2-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic
acid methyl ester
Example 230
[2-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-
acetic acid methyl ester
Example 231
3-(4-Bromo-phenyl)-1-{3-[4-(5-ethanesulfonyl-2-methoxycarbonylmethoxy-pheny
lamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-
5-carboxylic acid tert-butyl ester
Example 232
[2-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl
]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic
acid methyl ester
Example 233
1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-o-tolyloxy-piperidin-1-yl)-propyl]-
1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone
Example 234
1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-phenoxy-piperidin-1-yl)-propyl]-1,4
,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone
Example 235
1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-p-tolyloxy-piperidin-1-yl)-propyl]-
1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone
Example 236
1-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenoxy)-piperidin-1-yl]
-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 237
1-(3-(4-Bromo-phenyl)-1-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-
propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 238
1-(3-(4-Bromo-phenyl)-1-{3-[4-(3-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-
propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 239
1-(3-(4-Bromo-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydr
oxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 240
1-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-phenoxy-piperidin-1-yl)-p
ropyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone
Example 241
1-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-p-tolyloxy-piperidin-1-yl
)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone
Example 242
1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenoxy)-piper
idin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 243
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-
2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 244
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3-chloro-phenoxy)-piperidin-1-yl]-
2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 245
1-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-o-tolyloxy-piperidin-1-yl
)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone
Example 245
1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-
yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethan
one
Example 246
2-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yloxy)-benzonitrile
Example 247
2-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yloxy)-benzonitrile
Example 248
1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]p
yridin-1-yl]-3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-propan-2-ol
Example 249
1-[1-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-triflu
oromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone
Example 250
1-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-on
e
Example 251
1-{1-[3-(5-Acetyl-3-phenyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-
2-hydroxy-propyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one
Example 252
1-(1-{3-[5-Acetyl-3-(4-trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimi
dazol-2-one
Example 253
1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
Example 254
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimid
azol-2-one
Example 255
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
Example 256
1-(1-{3-[5-Acetyl-3-(4-chloro-3-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimida
zol-2-one
Example 257
1-(1-{3-[5-Acetyl-3-(4-trifluoromethylsulfanyl-phenyl)-4,5,6,7-tetrahydro-p
yrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-b
enzoimidazol-2-one
Example 258
1-(1-{3-[5-Acetyl-3-(4-methanesulfonyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimid
azol-2-one
Example 259
1(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidaz
ol-2-one
Example 260
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-
benzoimidazol-2-one
Example 261
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-b
enzoimidazol-2-one
Example 262
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-isopropyl-1,3-dihyd
ro-benzoimidazol-2-one
Example 263
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-butyl-1,3-dihydro-b
enzoimidazol-2-one
Example 264
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-benzyl-1,3-dihydro-
benzoimidazol-2-one
Example 265
1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-fluoro-1,3-dihydro-benzoimidaz
ol-2-one
Example 266
3-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-fluoro-2-oxo-2,3-dihydro-1H-be
nzoimidazole-4-carbonitrile
Example 267
1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro-1,3-dihydro-benzoimidaz
ol-2-one
Example 268
3-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyrid
in-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzoimidaz
ole-5-carbonitrile
Example 269
1-{2-Hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pr
opyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid amide
Example 270
1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one
Example 271
3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimid
azol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid methylamide
Example 272
3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimid
azol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi
ne-5-carboxylic acid ethylamide
Example 273
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-benzoimida
zol-2-one
Example 274
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methyl-1,3-dihydro-benzoimida
zol-2-one
Example 275
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5,6-dichloro-1,3-dihydro-benzoi
midazol-2-one
Example 276
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-
benzoimidazol-2-one
Example 277
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methyl-1,3-dihydro-
benzoimidazol-2-one
Example 278
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5,6-dichloro-1,3-dihy
dro-benzoimidazol-2-one
Example 279
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-
benzoimidazol-2-one
Example 280
1-(1-{3-[5-Acetyl-3-(4-chloro-3-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one
Example 281
1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-morphol
in-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one
Example 282
1-(1-{3-[5-Acetyl-3-(3-fluoro-4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-
benzoimidazol-2-one
Example 283
1-(1-{3-[5-Acetyl-3-(4-bromo-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimida
zol-2-one
Example 284
(R)-1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]
pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2
-one
Example 285
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-benzoimid
azol-2-one
Example 286
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-chloro-1,3-dihydro-benzoimida
zol-2-one
Example 287
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyrid
in-2-one
Example 288
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-methyl-1,3-dihydro-benzoimida
zol-2-one
Example 289
(R)-1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]
pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoi
midazol-2-one
Example 290
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-
2-one
Example 291
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
Example 292
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimida
zol-2-one
Example 293
(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihy
dro-benzoimidazol-2-one
Example 294
(R)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzo
imidazol-2-one
Example 295
(R)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihy
dro-benzoimidazol-2-one
Example 296
2-{2-[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyr
azolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihyd
ro-benzoimidazol-1-yl]-ethyl}-isoindole-1,3-dione
Example 297
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-amino-ethyl)-1,3
-dihydro-benzoimidazol-2-one
Example 298
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimida
zol-2-one
Example 299
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-benzoimidaz
ol-2-one
Example 300
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-
benzoimidazol-2-one
Example 301
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-b
enzoimidazol-2-one
Example 302
6-Chloro-1-(1-{3-[3-(4-chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-te
trahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3
-dihydro-benzoimidazol-2-one
Example 303
1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimid
azol-2-one
Example 304
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1-(2-morpholi
n-4-yl-ethyl)-1,3-dihydrobenzoimidazol-2-one
Example 305
[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-acetic acid ethyl ester
Example 306
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2,2,2-trifluoro-et
hyl)-1,3-dihydrobenzoimidazol-2-one
Example 307
[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]acetonitrile
Example 308
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-hydroxy-ethyl)-1
,3-dihydro-benzoimidazol-2-one
Example 309
1(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-b
enzoimidazol-2-one
Example 310
1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-
benzoimidazol-2-one
Example 311
1-Ethyl-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4
,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-
dihydro-benzoimidazol-2-one
Example 312
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3
-dihydro-benzoimidazol-2-one
Example 313
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-hydroxy-ethyl)-1
,3-dihydro-benzoimidazol-2-one
Example 314
3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4
,5-b]pyridin-2-one
Example 315
[3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-acetonitrile
Example 316
2-[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazo
lo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-
benzoimidazol-1-yl]-acetamide
Example 317
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-oxo-tetrahydro-f
uran-3-yl)-1,3-dihydro-benzoimidazol-2-one
Example 318
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-methoxy-ethyl)-1
,3-dihydro-benzoimidazol-2-one
Example 319
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-oxo-butyl)-1,3-d
ihydro-benzoimidazol-2-one
Example 320
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-diethylamino-eth
yl)-1,3-dihydro-benzoimidazol-2-one
Example 321
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-cyclopropylmethyl-1
,3-dihydro-benzoimidazol-2-one
Example 322
1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-methyl-allyl)-1,
3-dihydro-benzoimidazol-2-one
Example 323
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-
benzoimidazol-2-one
Example 324
5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-m
ethyl-1,3-dihydro-benzoimidazol-2-one
Example 325
6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3
-dihydro-benzoimidazol-2-one
Example 326
N-[4-(5-Acetyl-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-pip
eridin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-phe
nyl]-acetamide
Example 327
[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-acetic acid
Example 328
1-(1-{3-[5-Acetyl-3-(3-bromo-4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimida
zol-2-one
Example 329
3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-i
midazo[4,5-b]pyridin-2-one
Example 330
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3
-dihydro-imidazo[4,5-b]pyridin-2-one
Example 331
1-(1-{3-[5-(1H-Imidazole-4-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3
-dihydro-benzoimidazol-2-one
Example 332
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carboxylic acid amide
Example 333
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carboxylic acid ethylamide
Example 334
1-(1-{3-[5-(Isoxazole-5-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetr
ahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-di
hydro-benzoimidazol-2-one
Example 335
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-sulfonic acid (N-t-butoxycarbonyl)amide
Example 336
1-Methyl-3-(1-{3-[5-(5-methyl-isoxazole-3-carbonyl)-3-(4-trifluoromethyl-ph
enyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-y
l)-1,3-dihydro-benzoimidazol-2-one
Example 337
3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3
-dihydro-imidazo[4,5-b]pyridin-2-one
Example 338
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-i
midazo[4,5-b]pyridin-2-one
Example 339
5-Dimethylamino-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5
,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-meth
yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
Example 340
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-ethyl-5-methoxy-1,3-dihydro-im
idazo[4,5-b]pyridin-2-one
Example 341
1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
Example 342
1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimida
zol-2-one
Example 343
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-1-ethyl-5-methoxy-1,3-dihydro-imidazo[4,5
-b]pyridin-2-one
Example 344
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,
5-b]pyridin-2-one
Example 345
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carboxylic acid benzyl ester
Example 346
5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-p
henyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-
yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
Example 347
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-pro
pyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin
e-5-carbothioic acid methylamide
Example 348
3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-
piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbox
ylic acid phenylamide
Example 349
1-(1-{3-[5-Benzoyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one
Example 350
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidaz
ol-2-one
Example 351
1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimida
zol-2-one
Example 352
3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-b
enzoimidazol-2-one
Example 353
1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-
1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-
c]pyridine-5-carboxylic acid amide
Example 354
1-(1-{3-[3-(4-Bromo-phenyl)-5-phenylmethanesulfonyl-4,5,6,7-tetrahydro-pyra
zolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzo
imidazol-2-one
Example 355
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzo
imidazol-2-one
Example 356
3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-
piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbox
ylic acid amide
Example 357
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-benzoimidaz
ol-2-one
Example 358
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-be
nzoimidazol-2-one
Example 359
3-(4-Bromo-phenyl)-1-{3-[4-(6-chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidaz
ol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine
-5-carboxylic acid amide
Example 360
3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-
pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl-1,3-dihyd
ro-benzoimidazol-2-one
Example 361
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one
Example 362
3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-
piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfon
ic acid t-butoxycarbonyl-amide
Example 363
1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
Example 364
1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one
Example 365
3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin
-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic
acid t-butoxycarbonyl-amide
Example 366
3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin
-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid amide
Example 367
(R)-5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phen
yl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)
-1-methyl-1,3-dihydro-benzoimidazol-2-one
Example 368
1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c
]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2
-one
Example 369
1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyraz
olo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoi
midazol-2-one
Example 370
1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-1,3-dihydro
-benzoimidazol-2-one
Example 371
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,
5-b]pyridin-2-one
Example 372
3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4
,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-
imidazo[4,5-b]pyridin-2-one
Example 373
1-{2-Hydroxy-3-[4-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-
1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-
c]pyridine-5-carboxylic acid amide
Example 374
3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyrid
in-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine
-5-carboxylic acid amide
Example 375
[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-
tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-d
ihydro-imidazo[4,5-b]pyridin-1-yl]-acetonitrile
Example 376
3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-pipe
ridin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid methylamide
Example 377
3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyrid
in-2-one
Example 378
3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4
,5-b]pyridin-2-one
Example 379
[3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-ben
zoimidazol-1-yl]-acetic acid ethyl ester
Example 380
[3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo
[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-be
nzoimidazol-1-yl]-acetic acid ethyl ester
Example 381
[3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyr
idin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazo
l-1-yl]-acetic acid ethyl ester
Example 382
5-Chloro-3-(1-{3-[3-(3,4-dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahy
dro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihyd
ro-benzoimidazol-2-one
Example 383
(R)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6
,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl
-1,3-dihydro-benzoimidazol-2-one
Example 384
1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-pyridin-4-
ylmethyl-1,3-dihydro-benzoimidazol-2-one
Example 385
(R)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluorometh
yl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidi
n-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one
Example 386
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-3H-benzooxazol-2-one
Example 387
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-methyl-3H-benzooxazol-2-one
Example 388
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzooxazole-
6-carboxylic acid ethyl ester
Example 389
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-ethanesulfonyl-3H-benzooxazol
-2-one
Example 390
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-methyl-3H-benzooxaz
ol-2-one
Example 391
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-ben
zooxazole-6-carboxylic acid ethyl ester
Example 392
3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyri
din-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-3H-benzooxazol-2-one
Example 393
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-ethanesulfonyl-3H-b
enzooxazol-2-one
Example 394
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-3H-benzooxa
zol-2-one
Example 395
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-one
Example 396
3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[
4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-3H-benzooxaz
ol-2-one
Example 397
3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-t
etrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3H-oxazolo[4
,5-b]pyridin-2-one
Example 398
1-[1-[3-(4-Benzooxazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluor
omethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone
Example 399
1-[1-{2-Hydroxy-3-[4-(6-methyl-benzooxazol-2-yl)-piperidin-1-yl]-propyl}-3-
(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-
ethanone
Example 400
1-[1-{3-[4-(Benzothiazol-2-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-tr
ifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethan
one
Example 401
1-[1-{2-Hydroxy-3-[4-(5-methyl-benzooxazol-2-yl)-piperidin-1-yl]-propyl}-3-
trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-eth
anone
Example 402
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperidin-1-yl]
-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone
Example 403
3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pr
opyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbaldehyde
Example 404
1-[1-[3-(4-Benzo[b]thiophen-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-tri
fluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethano
ne
Example 405
1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-triflu
oromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-
ol
TABLE 3 EXAMPLE IC.sub.50 (.mu.M) 101 0.51 104 0.12 106 0.06 110
0.33 111 1.2 113 0.11 114 0.10 117 0.28 116 0.64 119 0.09 122 0.06
125 0.25 126 0.08 127 0.02 130 0.03 132 0.11 133 0.15 137 0.03 139
0.13 141 0.84 143 0.05 145 0.07 148 0.13 149 0.13 154 0.09 155 0.04
157 0.04 159 0.15 160 0.15 163 0.14 167 0.13 168 0.16 169 0.09 171
0.16 174 0.85 176 0.83 177 0.05 180 0.09 182 0.87 183 2.3 188 1.1
187 0.36 193 0.44 195 1.1 197 1.4 207 1.3 211 1.8 213 1.1 215 0.14
217 0.83 221 1.4 226 0.75 228 0.17 233 0.34 236 0.71 239 0.34 244
0.65 246 0.30 249 0.69 252 0.13 253 0.14 256 0.64 257 0.26 258 0.23
259 0.12 260 0.48 261 0.35 264 0.34 266 0.66 267 0.28 268 0.30 269
0.12 270 0.04 272 0.33 273 0.09 275 0.12 277 0.06 280 0.23 281 0.33
284 0.26 285 0.13 286 0.21 289 0.20 290 0.15 293 0.16 294 0.28 296
0.34 300 0.14 301 0.18 304 0.14 305 0.11 306 0.09 307 0.09 308 0.13
313 0.23 314 0.14 315 0.08 316 0.28 320 0.39 321 0.08 325 0.09 327
0.52 329 0.08 330 0.06 331 0.06 333 0.24 334 0.08 335 0.39 336 0.16
337 0.10 339 0.20 340 0.09 342 0.38 345 0.55 346 0.07 347 0.48 348
0.19 354 0.93 359 0.04 365 0.11 366 0.05 367 0.03 371 0.08 374 0.08
375 0.05 379 0.07 383 0.18 384 0.17 385 0.04 386 0.37 387 0.34 388
0.32 392 0.27 395 0.39 396 0.31 397 0.12 398 0.19 399 0.51 400 0.55
401 0.32
F. Other Embodiments
The features and advantages of the invention are apparent to one of
ordinary skill in the art. Based on this disclosure, including the
summary, detailed description, background, examples, and claims,
one of ordinary skill in the art will be able to make modifications
and adaptations to various conditions and usages. These other
embodiments are also within the scope of the invention.
* * * * *